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Publication numberUS6124463 A
Publication typeGrant
Application numberUS 09/333,161
Publication dateSep 26, 2000
Filing dateJun 14, 1999
Priority dateJul 2, 1998
Fee statusPaid
Also published asCA2335779A1, EP1091941A1, WO2000001675A1
Publication number09333161, 333161, US 6124463 A, US 6124463A, US-A-6124463, US6124463 A, US6124463A
InventorsJames Peter Beck, Matthew Allen Curry
Original AssigneeDupont Pharmaceuticals
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Treatment of affective disorder, anxiety or depression
US 6124463 A
Abstract
The present invention describes novel benzimidazoles of formula: ##STR1## or pharmaceutically acceptable salt forms thereof, which are useful as CRF antagonists.
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Claims(8)
What is claimed is:
1. A compound of formula (I): ##STR11## or a stereoisomer or pharmaceutically acceptable salt form thereof; wherein:
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group consisting of CH--R9, N--R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group consisting of C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, --SO2 --C1-10 alkyl, --SO2 --R1a, and --SO2 --R1b ;
R1 is substituted with 1 or more substituents selected from the group consisting of --CN, --S(O)n R14b, --COR13a, --CO2 R13a, --NR15a COR13a, --N(COR13a)2, --NR15a CONR13a R16a, NR15a CO2 R14b, --CONR13a R16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group --O--, --S(O)n --, --NR13a --, --NCO2 R14b --, --NCOR14b -- and --NSO2 R14b --, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R13a, CO2 R14b, COR14b and SO2 R14b ;
R1 is also substituted with 1-3 substituents independently selected at each occurrence from the group consisting of R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, --OR13a, --NR13a R16a, C1-4 alkoxy-C1-4 alkyl and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by --O--;
provided that R1 is other than a cyclohexyl-(CH2)2 -- group;
R1a is aryl and is selected from the group consisting of phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 --OR17 and 0-5 substituents independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, SH, --S(O)n R18, --COR17, --OC(O)R18, --NR15a COR17, --N(COR17)2, --NR15a CONR17a R19a, --NR15a CO2 R18, --NR17a R19a, and --CONR17a R19a ;
R1b is heteroaryl and is selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR17, SH, --S(O)m R18, --COR17, --OC(O)R18, --NR15a COR17, --N(COR17)2, --NR15a CONR17a R19a, --NR15a CO2 R18, --NR17a R19a, and --CONR17a R19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R15a, CO2 R14b, COR14b and SO2 R14b ;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR13a, SH, --S(O)n R14b, --COR13a, --OC(O)R14b, --NR15a COR13a, --N(COR13a)2, --NR15a CONR13a R16a, --NR15a CO2 R14b, --NR13a R16a, and --CONR13a R16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R13a, CO2 R14b, COR14b and SO2 R14b and wherein any sulfur atom is monooxidized or dioxidized;
provided that R1 is other than a --(CH2)1-4 -aryl, --(CH2)1-4 -heteroaryl, or --(CH2)1-4 -heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;
R2 is C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, or C2-4 alkynyl and is substituted with 0-3 substituents selected from the group consisting of --CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, --CN, CF3 or C2 F5 ;
R3, R7 and R8 are independently selected at each occurrence from the group consisting of H, Br, Cl, F, I, --CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2 amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2 amino;
provided that when R1 is unsubstituted C1-10 alkyl, then R3 is other than substituted or unsubstituted phenyl;
R9 and R10 are independently selected at each occurrence from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group consisting of H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)--, heteroaryl and heteroaryl(C1-4 alkyl)--;
R13a and R16a are independently selected at each occurrence from the group consisting of H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)--, heteroaryl and heteroaryl(C1-4 alkyl)-- and benzyl, benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 -cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14 S(O)n -C1-4 alkyl, and R17b R19b N--C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17 R9 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R13, CO2 R14, COR14 and SO2 R14 ;
alternatively, in an NR17b R19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R13, CO2 R14, COR14 and SO2 R14 ;
R17a and R19a are independently selected at each occurrence from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group consisting of phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, --OR17, Br, Cl, F, I, C1-4 haloalkyl, --CN, --NO2, SH, --S(O)n R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CONR17 R19, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF3, C2 F5, OCF3, SO2 Me and acetyl;
heteroaryl is independently selected at each occurrence from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR17, SH, --S(O)m R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CONR17 R19, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R15, CO2 R14a, COR14a and SO2 R14a ; and,
provided that when D is imidazole or triazole, R1 is other than unsubstituted C1-6 linear or branched alkyl or C3-6 cycloalkyl.
2. A compound according to claim 1, wherein:
R1 is C3-8 cycloalkyl or C3-6 cycloalkyl-C1-6 alkyl.
3. A compound according to claim 1, wherein:
D is a heteroaryl group attached through an unsaturated carbon atom.
4. A compound according to claim 1, wherein:
D is a phenyl group substituted with 3-5 substituents independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, --OR17, Br, Cl, F, I, C1-4 haloalkyl, --CN, --NO2, SH, --S(O)n R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CONR17 R19, --NR15 CO2 R18, --NR17 R19, --CONR17 R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF3, C2 F5, OCF3, SO2 Me and acetyl.
5. A compound according to claim 1, wherein:
R1 is C1-10 alkyl; and
R1 is substituted with 1-3 substituents selected from the group consisting of R1a, R1b, R1c, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, --OR13a, --NR13a R16a, --CN, --S(O)n R14b, --COR13a, --CO2 R13a, --NR15a COR13a, N(COR13a)2, NR15a CONR13a R16a, --NR15a CO2 R14b, --CONR13a R16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl wherein the N4 in the 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R13a, CO2 R14b, COR14b and SO2 R14b ; C3-8 cycloalkyl wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group consisting of --O--, --S(O)n --, --NR13a, --NCO2 R14b --, --NCOR14b -- and --NSO2 R14b --; and C3-8 cycloalkyl wherein the C3-8 cycloalkyl is substituted with 0-1 R9, and 0-1 carbons in the C3-8 cycloalkyl is replaced by --O--.
6. A compound according to claim 1, wherein the compound is selected from:
1-(1,1-Dicyclopropyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-(1,1-Dicyclopropyl)methyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-(1-cyclopropyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-cyclopentyl-2-ethyl-4-(2,4 ,5-trichlorophenyl)-6-methyl-1H-benzimidazole,
1-(1-phenyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-(1,1-diphenyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,
1-cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)benzimidazole,
1-(2-methyl)cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)-1H-benzimidazole,
1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4,6-trichlorophenyl)-1H-benzimidazole,
1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4-dichlorophenyl)-1H-benzimidazole
1-(1,1-dicyclopropyl) methyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,
1-(1-cyclopropyl)butyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,
1-cyclopentyl-2-ethyl-4-(2,4,6-trimethyl-3-pyridyl)-1H-benzimidazole.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1.
8. A method of treating a subject afflicted with affective disorder, anxiety or depression which comprises administering to the subject the pharmaceutical composition of claim 6.
Description

This application is a continuation of provisional patent application Ser. No. 60/091,575 filed on Jul. 2, 1998.

FIELD OF THE INVENTION

This invention relates to novel benzimidazoles, pharmaceutical compositions containing the same and methods of using same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing corticotropin releasing factor (CRF), including but not limited to disorders induced or facilitated by CRF.

BACKGROUND

Corticotropin releasing factor, a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohisto-chemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provides evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel benzimidazoles which are useful as CRF antagonists or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide a method for treating psychiatric disorders and neurological diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors, discovery that compounds of formula I: ##STR2## or pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R7, R8, X and D are defined below, are CRF antagonists.

DETAILED DESCRIPTION OF THE INVENTION

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR3## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

D is an aryl or heteroaryl group attached through an unsaturated carbon atom;

X is selected from the group CH--R9, N--R10, O, S(O)n and a bond;

n is 0, 1 or 2;

R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, --SO2 --C1-10 alkyl, --SO2 --R1a and --SO2 --R1b ;

R1 is substituted with 0-1 substituents selected from the group --CN, --S(O)n R14b, --COR13a, --CO2 R13a, --NR15a COR13a, --N(COR13a)2, --NR15a CONR13a R16a, --NR15a CO2 R14b, --CONR13a R16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group --O--, --S(O)n --, --NR13a --, --NCO2 R14b --, --NCOR14b -- and --NSO2 R14b --, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2 R14b, COR14b and SO2 R14b ;

R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, --OR13a, --NR13a R16a, C1-4 alkoxy-C1-4 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by --O--;

provided that R1 is other than a cyclohexyl--(CH2)2 -- group;

R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 --OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, SH, --S(O)n R18, --COR17, --OC(O)R18, --NR15a COR17, --N(COR17)2, --NR15a CONR17a R19a, --NR15a CO2 R8, --NR17a R19a, and --CONR17a R19a ;

R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR17, SH, --S(O)m R18, --COR17, --OC(O)R18, --NR15a COR17, --N(COR17)2, --NR15a CONR17a R19a, --NR15a CO2 R18, --NR17a R19a, and --CONR17a R19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2 R14b, COR14b and SO2 R14b ;

R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR13a, SH, --S(O)n R14b, --COR13a, --OC(O)R14b, --NR15a COR13a, --N(COR13a)2, --NR15a CONR13a R16a, --NR15a CO2 R14b, --NR13a R16a, and --CONR13a R16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2 R14b, COR14b and SO2 R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;

provided that R1 is other than a --(CH2)1-4 -aryl, --(CH2)1-4 -heteroaryl, or --(CH2)1-4 -heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;

R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group --CN, hydroxy, halo and C1-4 alkoxy;

alternatively R2, in the case where x is a bond, is selected from the group --CN, CF3 and C2 F5 ;

R3, R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, --CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2a amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2 amino; provided that when R1 is unsubstituted C1-10 alkyl, then R3 is other than substituted or unsubstituted phenyl;

R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;

R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)--, heteroaryl and heteroaryl (C1-4 alkyl)--;

R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;

R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)--, heteroaryl and heteroaryl(C1-4 alkyl)-- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;

R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;

R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;

R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;

R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;

R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14 S(O)n --C1-4 alkyl, and R17b R19b N--C2-4 alkyl;

R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;

alternatively, in an NR17 R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2 R14, COR14 and SO2 R14 ;

alternatively, in an NR17b R19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2 R14, COR14 and SO2 R14 ;

R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;

aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, --OR17, Br, Cl, F, I, C1-4 haloalkyl, --CN, --NO2, SH, --S(O)n R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CONR17 R19, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF3, C2 F5, OCF3, SO2 Me and acetyl;

heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, --CN, nitro, --OR17, SH, --S(O)m R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CONR17 R19, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2 R14a, COR14a and SO2 R14a ; and,

provided that when D is imidazole or triazole, R1 is other than unsubstituted C1-6 linear or branched alkyl or C3-6 cycloalkyl.

[2a] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

X is selected from the group O, S(O)n and a bond;

n is 0, 1 or 2;

R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C16 alkyl;

R1 is substituted with 0-1 substituents selected from the group --CN, --S(O)n R14b, --COR13a, --CO2 R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group --O--, --S(O)n --, --NR13a --, --NCO2 R14b --, --NCOR14b -- and --NSO2 R14b --;

R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2 CF3, --OR13a, --NR13a R16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by --O--;

provided that R1 is other than a cyclohexyl--(CH2)2 -- group;

R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 --OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, --CN, --S(O)n R18, --COR17, --NR17a R19a, and CONR17a R19a ;

R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, --CN, --OR17, --S(O)m R18, --COR17, --NR17a R19a, and --CONR17a R19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2 R14b, COR14b and SO2 R14b ;

provided that R1 is other than a --(CH2)1-4 -aryl or --(CH2)1-4 -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group --CN, OH, Cl, F, and C1-4 alkoxy;

R3, R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, --CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2 -amino;

R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;

R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)--, and heteroaryl(C1-2 alkyl)--;

R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;

R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)--, and heteroaryl(C1-2 alkyl)--;

R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;

R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;

R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;

R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;

R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;

alternatively, in an NR17 R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2 R14, COR14 and SO2 R14 ;

R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;

aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, --OR17, Br, Cl, F, C1-4 haloalkyl, --CN, --S(O)n Rl8, --COR17, --CO2 R17, --NR15 COR17, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 ; and,

heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, --CN, --OR17, --S(O)m R18, --COR17, --CO2 R17, --OC(O)R18, --NR15 COR17, --N(COR17)2, --NR15 CO2 R18, --NR17 R19, and --CONR17 R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R CO2 R14a, COR14a and SO2 R14a.

[2b] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

X is selected from the group O, S and a bond

R1 is selected from C1-6 alkyl, C3-8 cycloalkyl and C3-8 cycloalkyl-C1-6 alkyl;

R1 is substituted with 0-1 substituents selected from the group --CN, --CO2 R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group --O--, --S(O)n --, and --NR13a --; R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, --OR13a, --NR13a R16a, C1-2 alkoxy-C1-2 -alkyl, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by --O--;

provided that R1 is other than a cyclohexyl--(CH2)2 -- group;

R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, Br, Cl, F, CF3, --CN, SCH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2 ;

R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH (CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, CF3, --CN, SCH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2 CH3, COCH3 and SO2 CH3 ;

provided that R1 is other than a --(CH2)1-4 -aryl or --(CH2)1-4 -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R2 is selected from the group CH3, CH2 CH3, CH(CH3)2, and CH2 CH2 CH3 ;

R3 and R8 are independently selected at each occurrence from the group H, CH3, CH2 CH3, CH(CH3)2, and CH2 CH2 CH3 ;

aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, CF3, --CN, SCH3, --SO2 CH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2 ; and,

heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, CF3, --CN, SCH3, --SO2 CH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2 CH3, COCH3 and SO2 CH3.

[2c] In a still more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R1 is substituted C1 ;

R1 is substituted with 0-1 substituents selected from the group --CN, --CO2 CH3, and --CO2 CH2 CH3 ;

R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, --(CH2)3 CH3, --CH═CH2, --CH═CH(CH3), --CH═CH, --CH═C(CH3), --CH2 OCH3, --CH2 CH2 OCH3, F, CF3, cyclopropyl, CH3 -cyclopropyl, cyclobutyl, CH3 -cyclobutyl, cyclopentyl, CH3 -cyclopentyl;

R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2 CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, Br, Cl, F, CF3, --CN, and SCH3 ;

R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, OCH3, OCH2 CH3, OCF3, Br, Cl, F, CF3, --CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2 CH3, COCH3 and SO2 CH3 ;

provided that R1 is other than a --(CH2)1-4 -aryl or --(CH2)1-4 -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R2 is selected from the group CH3, CH2 OH3, and CH(CH3)2 ;

R3, R7 and R8 are independently selected at each occurrence from the group H and CH3 ;

aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, CF3, --CN, SCH3, SO2 CH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2 ; and,

heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, CF3, --CN, SCH3, SO2 CH3, --NH2, --NHCH3, --N(CH3)2, --C(O)NH2, --C(O)NHCH3, and --C(O)N(CH3)2.

[2d] In a further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R1 is substituted (cyclopropyl)-C1 alkyl or (cyclobutyl)-C1 alkyl;

R1 is substituted with 0-1 --CN;

R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, --(CH2)3 CH3, --CH═CH2, --CH═CH(CH3), --CH═CH, --CH═C(CH3), --CH2 OCH3, --CH2 CH2 OCH3, F, CF3, cyclopropyl, and CH3 -cyclopropyl;

R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2 CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, Br, Cl, F, CF3, --CN, and SCH3 ;

R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, OCH3, OCH2 CH3, OCF3, Br, Cl, F, CF3, --CN, and SCH3.

[2e] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)-C1 alkyl substituted with 1 substituent independently selected at each occurrence from the group R1a, R1b, CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, --(CH2)3 CH3, --CH═CH2, --CH═CH(CH3), --CH═CH, --CH═C(CH3), --CH2 OCH3, --CH2 CH2 OCH3, F, CF3, cyclopropyl, and CH3 -cyclopropyl;

R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2 CH3, Cl, F, and CF3 ;

R1b is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH3, OCH3, Cl, F, and CF3.

[2f] In an even further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R1 is selected from the group (cyclopropyl)CH--CH3, (cyclopropyl)CH--CH2 CH3, (cyclopropyl) CH--CH2 OCH3, (cyclopropyl) CH--CH2 CH2 CH3, (cyclopropyl) CH--CH2 CH2 OCH3, (cyclopropyl)2 CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH3 -furanyl)(cyclopropyl)CH, (cyclobutyl)CH--CH3, (cyclobutyl)CH--CH2 CH3, (cyclobutyl)CH--CH2 OCH3, (cyclobutyl)CH--CH2 CH2 CH3, (cyclobutyl)CH--CH2 CH2 OCH3, (cyclobutyl)2 CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH3 -furanyl)(cyclobutyl)CH;

[2g] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

D is phenyl substituted with 3-5 substituents independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH(CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, and CF3.

[2h] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2 CH3, CH(CH3)2, CH2 CH2 CH3, cyclopropyl, OCH3, OCH2 CH3, OCH (CH3)2, OCH2 CH2 CH3, OCF3, Br, Cl, F, and CF3.

[2i] In another preferred embodiment, R1 is other than a cyclohexyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group;

[2j] In another preferred embodiment, R1 is other than an aryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the aryl group is substituted or unsubstituted;

[2k] In another preferred embodiment, R1 is other than a heteroaryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the heteroaryl group is substituted or unsubstituted;

[2l] In another preferred embodiment, R1 is other than a heterocyclyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the heterocyclyl group is substituted or unsubstituted.

[2m] In another preferred embodiment, when D is imidazole or triazole, R1 is other than unsubstituted C1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linear or branched alkyl or C3, 4, 5, 6, 7, or 8 cycloalkyl.

[2n] In another preferred embodiment, R1a is not substituted with OR17.

[2o] In another preferred embodiment, the present invention provides a novel compound of formula I, wherein the compound is selected from:

1-(1-ethyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-ethyl)propyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-methyl)butyl-2-ethyl-4-(2,4,5-trichlorophenyl)-7-methyl-1H-benzimidazole,

1-(1-methyl)butyl-2-methyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-methyl)butyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-butyl)-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-carbmethoxy)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-carbmethoxy)ethyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-Dicyclopropyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-Dicyclopropyl)methyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-cyclopropyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-6-methyl-1H-benzimidazole,

1-(1-phenyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-diphenyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)benzimidazole,

1-(2-methyl)cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)-1H-benzimidazole,

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4,6-trichlorophenyl)-1H-benzimidazole,

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4-dichlorophenyl)-1H-benzimidazole

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,

1-(1-cyclopropyl)butyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,

1-(3-pentyl)-2-ethyl-4-(2,4-dimethyl-5-fluorophenyl)-1H-benzimidazole,

1-(2-pentyl)-2-ethyl-4-(2,4-dimethyl-5-fluorophenyl)-1H-benzimidazole,

1-(2-methyl)butyl-2-ethyl-4-(2,4-dichloro-5-fluorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,6-trimethyl-3-pyridyl)-1H-benzimidazole,

In another embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a method of treating psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in a mammal, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.

The CRF antagonist compounds provided by this invention and labelled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --Cv Fw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counter-ion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and Spiro compounds containing, for example, the above heterocycles.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.

The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The novel benzimidazoles of Formulae (I) of this invention may be prepared by one of the general schemes outlined below (Schemes 1-2). Compounds of Formulae (I) of this invention may be prepared as shown in Scheme I. An appropriately substituted 2-nitroaniline (II) is temporarily protected as the acetamide affording compounds of formula (III). The acetate is shown as example and is not intended to limit the choice of protecting groups at this position. The acetamide formation is typically conducted in the presence of acetic anhydride, although acetyl chloride may also be utilized. The reaction may be conducted in a wide array of typically utilized organic solvents, however, methylene chloride is generally preferred. Subsequent nitration, most commonly with chilled fuming nitric acid, affords in excellent yield the dinitro acetamide (IV). Details for this transformation may be found in the classical teachings of Vivian, etal. (J. Org. Chem. 1950, 20, 797).

Formation of compounds of formula (V) proceeds by hydrolysis of the acetamido group (see Green, T. W., Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991, p.351) and functional group interconversion of the amine to the bromide via either a Sandmeyer reaction or Gatterman reaction via the intermediacy of the corresponding diazonium ion. One familiar in the art of organic synthesis will readily understand the optimal conditions necessary to effect this transformation, and may consult the text of March, J. (Advanced Organic Chemistry, John Wiley and Sons, Inc., New York, N.Y., 1985, p.570 and p.647).

Compounds of formula (V) are reduced to the diamines of formula (VI) under a wide variety of potentially optimal conditions known to those skilled in the art. One may also consult the guide of Larock, R. C. (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, Inc., New York, N.Y., 1989, p.411). The cyclized compounds of formula (VII) may be synthesized by treatment of diamines of formula (VI) with an ortho acid derivative of the formula (alkyl--O)3 C--X--R2 where alkyl is preferably methyl, ethyl or propyl. The cyclizations are preferably carried out in the presence of an acid catalyst such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid or an organic acid such as, but not limited to, propionic acid. The reactions are conducted at room temperature or optionally at elevated temperature up to boiling to effect loss of (alkyl--OH) from the reaction.

Treatment of compounds of formula (VII) with a base and a compound of formula R1 -X wherein X represents a leaving group may afford the desired benzimidazole compounds of formula (VIII). Leaving groups may include, but are not limited to, bromo, chloro, iodo, cyano, alkoxy, methanesulfonyl, and p-toluenesulfonyl. Possible bases include, but are not limited to, the sodium, lithium or potassium bis(trimethylsilyl)amides, sodium or potassium hydride, alkyl lithiums and alkyl grignards and inorganic bases such as sodium, potassium and lithium hydroxide. The reactions are optionally conducted at room temperature or at elevated temperatures up to the boiling point of a cosolvent.

A wide variety of inert solvents may be employed, for example, dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, diethyl ether, and methylene chloride. The reactions may be successfully performed in glass reaction vessels or polypropylene wells, and one skilled in the art of organic chemistry will readily understand the optimal combinations of above conditions for effecting this transformation. Although regiomeric alkylation products are conceivable from tautomers of formula (VII), the experimental conditions taught herein will selectively provide the desired regiomer represented by compounds of formula (VIII). Alternatively, compounds of formula (VIII) may be formed under the classic conditions of the Mitsunobu reaction (Synthesis, 1980, p.1) from compounds of formula (VII) and an alcohol R1 --OH.

Finally, the benzimidazoles of formula (I) may be formed from precursors of formula (VIII) by treatment with boronic acids of formula D-B(OH)2 in the necessary presence of a palladium source, noteably Pd(OAc)2 with the additives triphenyl-phosphine and sodium carbonate. The preferred solvent of the Suzuki coupling is dimethoxyethane, although other inert organic solvents such as diethyl ether, and tetrahydrofuran may also be employed. The reaction is effected at room temperature or at temperatures up to the boiling point of the solvent. One skilled in the art will understand optimized conditions as taught by Larsen, R. D. (J. Org. Chem. 1994, 54, 6391-6394).

Alternatively, the benzimidazoles of formula (I) may also be prepared according to Scheme 2. A similiar teaching also appears in EP 0812831 (vide supra). Thus, under conditions taught in Scheme 1, the aryl bromides of formula (IX) are coupled to reagents of formula D-B(OH)2 to afford compounds of formula (X). For the preparation of compounds of formula (IX), one may refer to the art of Peet, etal. (J. Heterocyclic Chem. 1979, 16, 33-39) for details (R3 ═R7 ═R8 ═H). Hydrolysis of the carboalkoxy of compounds of formula (X) under conditions familiar to anyone in the art affords the acid derivatives of formula (XI) which are then subjected to a modified Curtius rearrangement (see March, J., Advanced Organic Chemistry, John Wiley and Sons, Inc., New York, N.Y., 1985, p.984) in the presence of diphenylphosphoryl azide and a trialkyl amine base in an inert solvent (ie. dry benzene, dry toluene). The reaction is preferrably refluxed for one hour, cooled and treated with t-butanol and heated for an additional 2-24 hours to effect incorporation of the t-butyl carbamate, providing compounds of formula (XII, PG═Boc).

Reduction of compounds of formula (XII) under a wide variety of methods known to those skilled in the art affords cleanly the aryl diamines of formula (XIII). Common reduction methods include hydrogenation in the presence of a catalyst such as Raney nickel (RaNi) or palladium on carbon (Pd/C) in an inert alcohol solvent (methanol, ethanol) or ethyl acetate. The reactions are optionally run under pressure and at elevated temperature (60 C.). Alternatively, and preferably, the reduction may be effected in exceptionally high yield by treatment of compounds of formula (XII) with sodium dithionite in the presence of ammonium hydroxide. One optimal solvent combination for this reduction is a mixture of dioxane/water (1:1).

Formation of compounds of formula (XIV) is achieved by a common reductive amination procedure employing compounds of formula (XIII) and the appropriate R1 aldehydes and ketones. The reaction is preferably conducted under anhydrous conditions in the presence of a dehydrating agent (ie, sodium sulfate, magnesium sulfate) and acid catalyst (ie. hydrochloric acid, sulfuric acid, or acetic acid). Examples of suitable reducing agents which are intended to exemplify and not limit the invention are sodium triacetoxyborohydride and sodium cyanoborohydride. Compounds of formula (XIV) are then deprotected under common conditions (PG═Boc, see, Green, T. W. Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991, p.328) to afford pre-cyclization compounds of formula (XV).

Finally, the desired benzimidazoles of formula (I) are readily afforded from compounds of formula (XV) as described in Scheme 1 for the formation of (I) from compounds of formula (VIII). ##STR4##

The following example is provided to describe the invention in further detail. The example, which sets forth the best mode presently contemplated for carrying out the invention, is intended to illustrate and not to limit the invention.

EXAMPLE 1 2-Ethyl-1-(1-ethyl-propyl)-4-(2,4,5-trichloro-phenyl)-1H-benzimidazole

Step A:

2'; 4', 5'-Trichloro-3-nitro-biphenyl-2-carboxylic acid methyl ester

Under a nitrogen atmosphere in 15 ml of anhydrous dimethoxyethane (DME) was dissolved 461 mg (1.76 mmol) triphenylphosphine. The reaction was evacuated and repressurized under nitrogen and stirred for 15 minutes at which point 98.55 mg of palladium acetate was added. The reaction was stirred for an additional 15 minutes at which point 1.10 g (4.88 mmol) of 2,4,5-trichlorophenylboronic acid was added. The reaction was stirred another 15 minutes at which time 1.14 g (4.39 mmol) of methyl 2-bromo-5-nitrobenzoate and 5 ml of 2N sodium carbonate were added. The reaction was evacuated and repressurized under nitrogen and heated to reflux for 18 hours at which time it was cooled, poured into 250 ml water, and extracted with ethyl acetate (350 ml). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the crude product as a brown oil. The crude product was purified by column chromatography on silica gel (275 g) and eluted with 20% ethyl acetate in hexanes to afford 740 mg (47%) of the title compound.

1 H NMR (CDCl3) 8.22 (dd, 1H, J=7 Hz, 1 Hz), 7.61 (m, 3H), 7.41 (s, 1H), 3.74 (s, 3H).

Step B:

2', 4', 5'-Trichloro-3-nitro-biphenyl-2-carboxylic acid

Under a nitrogen atmosphere was combined 735 mg (2.03 mmol) of the title compound Step A, 5 ml of tetrahydrofuran (THF), 3 ml of methanol, and 5 ml of water. To this solution was added 320 mg (8 mmol) of freshly powdered sodium hydroxide and the resulting solution was heated to reflux for 90 minutes. The reaction was cooled and concentrated in vacuo, diluted with 40 ml water and extracted with ethyl acetate (125 ml). After separation the aqueous layer was acidified to pH <2 with 6.25N hydrochloric acid (HCl) and extracted with ethyl acetate (325 ml). The combined organic extracts from the acidified water layer were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 700 mg (100%) of the title compound.

1 H NMR (CDCl3) 8.23 (dd, 1H, J=7 Hz, 1 Hz), 7.61 (m, 3H), 7.26 (s, 1H). HRMS (M-H)- calcd for C16 H5 Cl3 N1 O 343.9284, found 343.9297.

Step C:

(2', 4', 5'-Trichloro-3-nitro-biphenyl-2-yl)-carbamic acid tert-butyl ester

Under a nitrogen atmosphere in 20 ml of anhydrous benzene was combined 700 mg (2.03 mmol) of the title compound in Step B and 2.03 ml of triethylamine (TEA). To this solution was added 437 ml (2.03 mmol) of diphenylphosphoryl azide, and the resulting solution was heated to reflux for 1 hour. After completion the reaction mixture was cooled and 301 mg (4.06 mmol) of t-butanol was added, and the solution was heated to reflux for an additional 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (200 g) and eluted using 20% ethyl acetate in hexanes to afford 502 mg (59%) of the title compound as a light yellow solid.

1 H NMR (CDCl3) 8.06 (dd, 1H, J=7 Hz, 1.5 Hz), 7.62 (s, 1H), 7.49 (m, 3H), 1.28 (s, 9H). HRMS (M-H)- calcd for C17 H14 Cl3 N2 O 415.0019, found 415.0014.

Step D:

(3-Amino-2',4',5'-trichloro-biphenyl-2-yl)-carbamic acid tert-butyl ester

To 12 ml of a 1:1 solution of dioxane and water was added 500 mg (1.2 mmol) of the title compound in Step C and 0.6 ml of concentrated ammonium hydroxide. To this suspension was added 1.67 g (9.6 mmol) of sodium dithionite. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The resulting oil was dissolved in 1:1 ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate (225 ml) and the combined organic extracts dried over magnesium sulfate, filtered, and evaporated to yield 536.6 mg (100%) of the title compound as a beige solid. 1H NMR (DMSO d6) 8.00 (br s, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 6.98 (t, 1H, J=8 Hz), 6.74 (d, 1H, i═7.5 Hz), 6.43 (d, 1H, J=7 Hz), 1.16 (br s, 9H). HRMS (M+H)+ calcd for C17 H18Cl3 N2 O2 387.0433, found 387.0421.

Step E:

[3(1-Ethyl-propylamino)-2',4',5'-trichloro-binhenyl-2-yl]-carbamic acid tert-butyl ester

Under a nitrogen atmosphere was combined 5 ml of acetic acid, 232 mg (0.6 mmol) of the title compound in Step D and 122 ml of 3-pentanone. To this solution was added 853 mg (6 mmol) of sodium sulfate. The solution was stirred at room temperature for 25 minutes at which time 153 mg (0.72 mmol) of sodiumtriacetoxyborohydride was added. The reaction was allowed to stir at room temperature for an additional 1 hour and then quenched with aqueous sodium carbonate (100 ml) and extracted with ethyl acetate (320 ml). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford the crude product as a light brown oil. The crude product was purified by column chromatography on silica gel (30 g) and eluted with 20% ethyl acetate in hexanes to afford 171 mg (62%) of the title compound.

1 H NMR (CDCl3) 7.55 (s, 1H), 7,41 (br s, 1H), 7.21 (t, 1H, J=8 Hz), 6.71 (d, 1H, J=8 Hz), 6.46 (d, 1H, J=7 Hz), 3.32 (m, 1H), 1.58 (m, 4H), 1.3 (S, 9H), 0.9 (m, 6H). HRMS (M+H)+ calcd for C22 H28 Cl3 N2 O2 457.1216, found 457.1211.

Step F:

N-3-(1-Ethyl-propylamino)-2',4',5'-trichloro-biphenyl-2,3-diamine

Under a nitrogen atmosphere was dissolved 171 mg (0.37 mmol) of the title compound in Step E in 1 ml of dichloromethane and the resulting solution chilled to 0 C. Trifluoroacetic acid (12 ml) was added dropwise over 4 minutes and the reaction stirred at 0 C. for 1 hour and then allowed to warm to room temperature and stir for an additional 1 hour. Reaction was then evaporated in vacuo and the residual oil taken up in dichloromethane. The organic layer was washed with 1N sodium hydroxide (125 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (225 ml) and the combined organic extracts dried over sodium sulfate filtered and evaporated to yield 129 mg (99%) of the product as a brown oil.

.sup. 1H NMR (CDCl3) 7.62 (S, 1H), 7.46 (S, 1H), 6.86 (t, 1H, J=8 Hz), 6.69 (d, 1H, J=7 Hz), 6.48 (d, 1H, J=6 Hz), 3.25 (m, 1H), 1.60 (m, 4H), 0.95 (m, 6H). HRMS (M+H)+ calcd for C17 H20 Cl3 N2 357.0692, found 357.0693.

Step G:

2-Ethyl-1-(1-ethyl-propyl)-4-(2,4,5-trichloro-phenyl)-1H-benzimidazole

Under a nitrogen atmosphere was combined 129 mg (0.36 mmol) of the title compound of Step F in 5 ml of triethylorthopropionate. To the resulting solution was added 2 drops of concentrated hydrochloric acid. The reaction was allowed to stir at room temperature for 8 hours and then poured into 100 ml of water. The reaction was extracted with ethyl acetate (420 ml) and the combined organic extracts dried over sodium sulfate, filtered, and evaporated to yield the crude product as a light brown crystal. The crude product was purified by column chromatography on silica gel (20 g) and eluted with 20% ethyl acetate in hexanes to yield 101 mg (71%) of the title compound as a brown solid. M.P. =150.0-151.5 C.; .sup. 1H NMR (CDCl3) 7.72 (s, 1H), 7.61 (s, 1H), 7.52 (m, 1H), 7.20 (m, 2H), 4.10 (m, 1H), 2.92 (q, 2H, J=8 Hz), 2.18 (m, 2H), 2.05 (m, 2H), 1.38 (t, 3H, J=8 Hz), 0.83 (t, 6H, J=7.5 Hz); HRMS calc. for C20 H21 N2 Cl3 : (M+H)+ 395.0849, Found 395.0846; Anal Calcd for C20 H21 N2 Cl3 : C, 60.70; H, 5.358; N, 7.088. Found C, 60.40; H, 5.46; N, 6.75.

The foregoing tables contain further examples which are meant to be illustrative of the present invention, and not to be taken as limiting thereof.

                                  TABLE 1__________________________________________________________________________  #STR5##   -Ex.   R1    X   R2                  R3                      R7                         R8                             Mass Spec__________________________________________________________________________1  CH(CH2 CH3)2         CH2             CH3                  H   H  H   395.09  2 CH(CH2 CH3)2 CH2 CH3 CH3 H H  3 CH(CH2 CH3)2 CH2 CH3 H CH3 H  4 CH(CH2 CH3)2 CH2 H H H H  5 CH(CH2 CH3)2 O CH3 H H H  6 CH(CH2 CH3)2 O CH3 H H CH3  7 CH(CH2 CH3)2 CH2 CH2 CH3 H H H  8 CH(CH3)CH2 CH2 CH3 CH2 CH3 H CH3 H  9 CH(CH3)CH2 CH2 CH3 CH2 H H H H  10 CH(CH3)CH2 CH2 CH3 O CH3 H H H  11 CH(CH3)CH2 CH2 CH3 O CH3 H H CH3                              12 CH2 CH2 CH3 CH2                             CH3 H H H  13 CH2 CH2 CH2 CH3 CH2 CH3 H H H  14 CH2 CH(CH2 CH3)2 CH2 CH3 H H H                              15 CH2 CH2 CH(CH3)2                              CH2 CH3 H H H  16 CH(CO2 CH3)CH2 CH3 CH2 CH3 H H H                              17 CH(CO2 CH2 CH3)CH.sub                             .3 CH2 CH3 H H H  18 CH(COCH3)CH2 CH3 CH2 CH3 H H H  19 CH(COPh)CH2 CH3 CH2 CH3 H H H  20 CH2 CH2 C.tbd.CCH3 CH2 CH3 H H H  21 CH(cyclo-Pr)2 CH2 CH3 H H H  22 CH(cyclo-Pr)2 CH2 CH3 CH3 H H  23 CH(cyclo-Pr)2 CH2 CH3 H CH3 H  24 CH(cyclo-Pr)2 CH2 H H H H  25 CH(cyclo-Pr)2 CH2 H H CH3 H  26 CH(cyclo-Pr)2 O CH3 H H CH3  27 CH(cyclo-Pr)2 O CH3 H H H  28 CH(cyclo-Pr)2 CH2 CH2 CH3 H H H  29 CH2 cyclopropyl CH2 CH3 H H H  30 CH2 cyclopropyl CH2 CH3 CH3 H H  31 CH2 cyclopropyl CH2 CH3 H CH3 H  32 CH(Et)(c-Pr) CH2 CH3 H H H  33 CH(Et)(c-Pr) CH2 CH3 CH3 H H  34 CH(Et)(c-Pr) CH2 CH3 H CH3 H  35 CH(Et)(c-Pr) CH2 H H H H  36 CH2 CH2 OCH2 CH3 CH2 CH3 H H H                              37 CH2 CH2 OCH2                             CH3 CH2 H H H H  38 CH2 CH2 OCH2 CH3 O CH3 H H H  39 cyclopentyl CH2 CH3 H H H  40 cyclopentyl CH2 CH3 Me H H  41 cyclohexyl CH2 CH3 H H H  42 cyclohexyl CH2 CH3 H Me H  43 CH2 Ph CH2 CH3 H H H  44 CH2 Ph O CH3 H H H  45 CH(Ph)CH2 CH3 CH2 CH3 H H H  46 CH(Ph)2 CH2 CH3 H H H  47 CH2 -(2-chloroPh) CH2 CH3 H H H  48 CH2 -(4-chloroPh) CH2 CH3 H H H  49 CH2 -(4-MeO--Ph) CH2 CH3 H H H  50 CH2 -(4-CF3 O--Ph) CH2 CH3 H H H__________________________________________________________________________

              TABLE 2______________________________________  #STR6##  Ex.    R1        D______________________________________1    cyclopentyl    2,4,6-trimethylphenyl  2 cyclohexyl 2,4,6-trimethylphenyl  3 2-methyl(c-pentyl) 2,4,6-trimethylphenyl  4 benzyl 2,4,6-trimethylphenyl  5 2-chlorobenzyl 2,4,6-trimethylphenyl  6 4-chlorobenzyl 2,4,6-trichlorophenyl  7 CH(cyclopropyl)2 2,4,6-trichlorophenyl  8 4-fluorobenzyl 2,4-dichlorophenyl  9 CH(cyclopropyl)2 2-chloro-4-bromophenyl  10 4-bromobenzyl 2-chloro-4-bromophenyl  11 4-methoxybenzyl 2-chloro-4-bromophenyl  12 CH(cyclopropyl)2 2-thiomethyl-4-bromophenyl  13 CH(cyclopropyl)2 2-methyl-4-methoxyphenyl  14 CH(c-Pr)CH2 CH2 CH3 2-methyl-4-methoxyphenyl  15 CH2 CH2 CH2 CH3 2,4-dimethyl-5-fluorophenyl                16 CH(CH2 CH3)2 2,4-dimethyl-5-fluorop               henyl  17 CH(CH3)CH2 CH2 CH3 2,4-dimethyl-5-fluorophenyl                18 CH2 CH(CH3)CH2 CH3 2,4-dichlor               o-5-fluorophenyl  19 CH2 CH2 OCH2 CH3 2,4-dichloro-5-fluorophenyl                20 CH(Ph)(c-Pr) 2-bromo-4-dimethylaminophenyl                21 CH(4-F--Ph)(c-Pr) 2-methyl-4-dimethylaminophenyl                22 cyclopentyl 2,4,6-trimethyl-3-pyridyl  23 cyclohexyl 2,4,6-trimethyl-3-pyridyl  24 2-methyl(c-pentyl) 2,4,6-trimethyl-3-pyridyl  25 benzyl 2,4,6-trimethyl-3-pyridyl  26 CH(CH2 CH3)2 2,4,6-trimethyl-3-pyridyl  27 cyclopentyl 2,4-dimethyl-3-pyridyl  28 cyclohexyl 4,6-dimethyl-3-pyridyl  29 2-methyl(c-pentyl) 2,4-dimethoxy-3-pyridyl  30 benzyl 2-methyl-4-dimethylamino-3-pyridyl  31 2-methyl(c-pentyl) 6-methyl-4-dimethylamino-3-pyridyl  32 benzyl 2,4,6-trimethyl-3,5-pyrimidyl  33 CH(CH2 CH3)2 2,4-dimethyl-3,5-pyrimidyl  34 cyclopentyl 4-isopropyl-2-furanyl  35 cyclohexyl 5-isopropyl-2-furanyl  36 2-methyl(c-pentyl) 4-isopropyl-2-thiophenyl  37 benzyl 5-isopropyl-2-thiophenyl______________________________________

              TABLE 3______________________________________  #STR7##   - a1 R2 X = CH3 O  a2 R2 X = CH3 S  a3 R2 X = Me  a4 R2 X = Et  a5 R2 X = n-Pr   -  #STR8##   - b1 R2 X = CH3 O  b2 R2 X = CH3 S  b3 R2 X = Me  b4 R2 X = Et  b5 R2 X = n-Pr   -  #STR9##   - c1 R2 X = CH3 O  c2 R2 X = CH3 S  c3 R2 X = Me  c4 R2 X = Et  c5 R2 X = n-Pr   -  #STR10##   - d1 R2 X = CH3 O  d2 R2 X = CH3 S  d3 R2 X = Me  d4 R2 X = Et  d5 R2 X = n-Pr______________________________________  Ex. #   R1           D______________________________________   1 (cPr)2 CH 2-Cl-4-MeO-phenyl   2 phenyl(cPr)CH 2-Cl-4-MeO-phenyl   3 2-furanyl(cPr)CH 2-Cl-4-MeO-phenyl   4 3-furan(cPr)CH 2-Cl-4-MeO-phenyl   5 2-thienyl(cPr)CH 2-Cl-4-MeO-phenyl   6 3-thienyl(cPr)CH 2-Cl-4-MeO-phenyl   7 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-phenyl   8 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-MeO-phenyl   9 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-MeO-phenyl   10 cPr-CH(CH3) 2-Cl-4-MeO-phenyl   11 1-cPr-CH(CH2 CH3) 2-Cl-4-MeO-phenyl   12 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-MeO-phenyl   13 1-cPr-CH(CH2 OCH3) 2-Cl-4-MeO-phenyl   14 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-MeO-phenyl   15 (cBu)2 CH 2-Cl-4-MeO-phenyl   16 phenyl(cBu)CH 2-Cl-4-MeO-phenyl   17 2-furanyl(cBu)CH 2-Cl-4-MeO-phenyl   18 3-furan(cBu)CH 2-Cl-4-MeO-phenyl   19 2-thienyl(cBu)CH 2-Cl-4-MeO-phenyl   20 3-thienyl(cBu)CH 2-Cl-4-MeO-phenyl   21 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-phenyl   22 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-MeO-phenyl   23 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-MeO-phenyl   24 cBu-CH(CH3) 2-Cl-4-MeO-phenyl   25 1-cBu-CH(CH2 CH3) 2-Cl-4-MeO-phenyl   26 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-MeO-phenyl   27 1-cBu-CH(CH2 OCH3) 2-Cl-4-MeO-phenyl   28 1-cBu-CH (CH2 CH2 OCH3) 2-Cl-4-MeO-phenyl   29 (cPr)2 CH 2-Cl-4-CF3 -phenyl   30 phenyl(cPr)CH 2-Cl-4-CF3 -phenyl   31 2-furanyl(cPr)CH 2-Cl-4-CF3 -phenyl   32 3-furan(cPr)CH 2-Cl-4-CF3 -phenyl   33 2-thienyl(cPr)CH 2-Cl-4-CF3 -phenyl   34 3-thienyl(cPr)CH 2-Cl-4-CF3 -phenyl   35 2-isoxazolyl(cPr)CH 2-Cl-4-CF3 -phenyl   36 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-CF3 -phenyl   37 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-CF3 -phenyl   38 cPr-CH(CH3) 2-Cl-4-CF3 -phenyl   39 1-cPr-CH(CH2 CH3) 2-Cl-4-CF3 -phenyl   40 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-CF3 -phenyl                         41 1-cPr-CH(CH2 OCH3) 2-Cl-4-CF.su                       b.3 -phenyl   42 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-CF3 -phenyl                         43 (cBu)2 CH 2-Cl-4-CF3 -phenyl                         44 phenyl(cBu)CH 2-Cl-4-CF3 -phenyl                         45 2-furanyl(cBu)CH 2-Cl-4-CF3 -phenyl   46 3-furan(cBu)CH 2-Cl-4-CF3 -phenyl   47 2-thienyl(cBu)CH 2-Cl-4-CF3 -phenyl   48 3-thienyl(cBu)CH 2-Cl-4-CF3 -phenyl   49 2-isoxazolyl(cBu)CH 2-Cl-4-CF3 -phenyl   50 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-CF3 -phenyl   51 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-CF3 -phenyl   52 cBu-CH(CH3) 2-Cl-4-CF3 -phenyl   53 1-cBu-CH(CH2 CH3) 2-Cl-4-CF3 -phenyl   54 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-CF3 -phenyl                         55 1-cBu-CH(CH2 OCH3) 2-Cl-4-CF.su                       b.3 -phenyl   56 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-CF3 -phenyl                         57 (cPr)2 CH 2,4-diCl-phenyl   58 phenyl(cPr)CH 2,4-diCl-phenyl   59 2-furanyl(cPr)CH 2,4-diCl-phenyl   60 3-furan(cPr)CH 2,4-diCl-phenyl   61 2-thienyl (cPr)CH 2,4-diCl-phenyl   62 3-thienyl(cPr)CH 2,4-diCl-phenyl   63 2-isoxazolyl(cPr)CH 2,4-diCl-phenyl   64 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCl-phenyl   65 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCl-phenyl   66 cPr-CH(CH3) 2,4-diCl-phenyl   67 1-cPr-CH(CH2 CH3) 2,4-diCl-phenyl   68 1-cPr-CH(CH2 CH2 CH3) 2,4-diCl-phenyl   69 1-cPr-CH(CH2 OCH3) 2,4-diCl-phenyl   70 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCl-phenyl   71 (cBu)2 CH 2,4-diCl-phenyl   72 phenyl(cBu)CH 2,4-diCl-phenyl   73 2-furanyl(cBu)CH 2,4-diCl-phenyl   74 3-furan(cBu)CH 2,4-diCl-phenyl   75 2-thienyl(cBu)CH 2,4-diCl-phenyl   76 3-thienyl(cBu)CH 2,4-diCl-phenyl   77 2-isoxazolyl(cBu)CH 2,4-diCl-phenyl   78 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCl-phenyl   79 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCl-phenyl   80 cBu-CH(CH3) 2,4-diCl-phenyl   81 1-cBu-CH(CH2 CH3) 2,4-diCl-phenyl   82 1-cBu-CH(CH2 CH2 CH3) 2,4-diCl-phenyl   83 1-cBu-CH (CH2 OCH3) 2,4-diCl-phenyl   84 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCl-phenyl   85 (cPr)2 CH 2,5-diCl-phenyl   86 phenyl(cPr)CH 2,5-diCl-phenyl   87 2-furanyl(cPr)CH 2,5-diCl-phenyl   88 3-furan(cPr)CH 2,5-diCl-phenyl   89 2-thienyl(cPr)CH 2,5-diCl-phenyl   90 3-thienyl(cPr)CH 2,5-diCl-phenyl   91 2-isoxazolyl(cPr)CH 2,5-diCl-phenyl   92 2-(5-CH3 -furanyl)(cPr)CH 2,5-diCl-phenyl   93 2-(4-CH3 -isoxazolyl)(cPr)CH 2,5-diCl-phenyl   94 cPr-CH(CH3) 2,5-diCl-phenyl   95 1-cPr-CH(CH2 CH3) 2,5-diCl-phenyl   96 1-cPr-CH(CH2 CH2 CH3) 2,5-diCl-phenyl   97 1-cPr-CH(CH2 OCH3) 2,5-diCl-phenyl   98 1-cPr-CH(CH2 CH2 OCH3) 2,5-diCl-phenyl   99 (cBu)2 CH 2,5-diCl-phenyl  100 phenyl(cBu)CH 2,5-diCl-phenyl  101 2-furanyl(cBu)CH 2,5-diCl-phenyl  102 3-furan(cBu)CH 2,5-diCl-phenyl  103 2-thienyl (cBu)CH 2,5-diCl-phenyl  104 3-thienyl(cBu)CH 2,5-diCl-phenyl  105 2-isoxazolyl(cBu)CH 2,5-diCl-phenyl  106 2-(5-CH3 -furanyl)(cBu)CH 2,5-diCl-phenyl  107 2-(4-CH3 -isoxazolyl)(cBu)CH 2,5-diCl-phenyl  108 cBu-CH(CH3) 2,5-diCl-phenyl  109 1-cBu-CH(CH2 CH3) 2,5-diCl-phenyl  110 1-cBu-CH(CH2 CH2 CH3) 2,5-diCl-phenyl  111 1-cBu-CH(CH2 OCH3) 2,5-diCl-phenyl  112 1-cBu-CH(CH2 CH2 OCH3) 2,5-diCl-phenyl  113 (cPr)2 CH 2-Cl-4-CF3 O-phenyl  114 phenyl(cPr) CH 2-Cl-4-CF3 O-phenyl  115 2-furanyl(cPr)CH 2-Cl-4-CF3 O-phenyl  116 3-furan(cPr)CH 2-Cl-4-CF3 O-phenyl  117 2-thienyl(cPr)CH 2-Cl-4-CF3 O-phenyl  118 3-thienyl(cPr)CH 2-Cl-4-CF3 O-phenyl  119 2-isoxazolyl(cPr)CH 2-Cl-4-CF3 O-phenyl  120 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-CF3 O-phenyl  121 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-CF3 O-phenyl  122 cPr-CH(CH3) 2-Cl-4-CF3 O-phenyl  123 1-cPr-CH(CH2 CH3) 2-Cl-4-CF3 O-phenyl  124 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-CF3 O-phenyl                        125 1-cPr-CH(CH2 OCH3) 2-Cl-4-CF.su                       b.3 O-phenyl  126 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-CF3 O-phenyl                        127 (cBu)2 CH 2-Cl-4-CF3 O-phenyl                        128 phenyl(cBu)CH 2-Cl-4-CF3 O-phenyl                        129 2-furanyl(cBu)CH 2-Cl-4-CF3                       O-phenyl  130 3-furan(cBu)CH 2-Cl-4-CF3 O-phenyl  131 2-thienyl(cBu)CH 2-Cl-4-CF3 O-phenyl  132 3-thienyl(cBu)CH 2-Cl-4-CF3 O-phenyl  133 2-isoxazolyl(cBu)CH 2-Cl-4-CF3 O-phenyl  134 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-CF3 O-phenyl  135 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-CF3 O-phenyl  136 cBu-CH(CH3) 2-Cl-4-CF3 O-phenyl  137 1-cBu-CH(CH2 CH3) 2-Cl-4-CF3 O-phenyl  138 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-CF3 O-phenyl                        139 1-cBu-CH(CH2 OCH3) 2-Cl-4-CF.su                       b.3 O-phenyl  140 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-CF3 O-phenyl                        141 (cPr)2 CH 2-Cl-4-CH3 -phenyl                        142 phenyl(cPr)CH 2-Cl-4-CH3 -phenyl                        143 2-furanyl(cPr)CH 2-Cl-4-CH3 -phenyl  144 3-furan(cPr)CH 2-Cl-4-CH3 -phenyl  145 2-thienyl(cPr)CH 2-Cl-4-CH3 -phenyl  146 3-thienyl(cPr)CH 2-Cl-4-CH3 -phenyl  147 2-isoxazoly1(cPr)CH 2-Cl-4-CH3 -phenyl  148 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-CH3 -phenyl  149 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-CH3 -phenyl  150 cPr-CH(CH3) 2-Cl-4-CH3 -phenyl  151 1-cPr-CH(CH2 CH3) 2-Cl-4-CH3 -phenyl  152 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-CH3 -phenyl                        153 1-cPr-CH(CH2 OCH3) 2-Cl-4-CH.su                       b.3 -phenyl  154 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-CH3 -phenyl                        155 (cBu)2 CH 2-Cl-4-CH3 -phenyl                        156 phenyl(cBu)CH 2-Cl-4-CH3 -phenyl                        157 2-furanyl(cBu)CH 2-Cl-4-CH3 -phenyl  158 3-furan(cBu)CH 2-Cl-4-CH3 -phenyl  159 2-thienyl(cBu)CH 2-Cl-4-CH3 -phenyl  160 3-thienyl(cBu)CH 2-Cl-4-CH3 -phenyl  161 2-isoxazolyl(cBu)CH 2-Cl-4-CH3 -phenyl  162 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-CH3 -phenyl  163 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-CH3 -phenyl  164 cBu-CH(CH3) 2-Cl-4-CH3 -phenyl  165 1-cBu-CH(CH2 CH3) 2-Cl-4-CH3 -phenyl  166 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-CH3 -phenyl                        167 1-cBu-CH(CH2 OCH3) 2-Cl-4-CH.su                       b.3 -phenyl  168 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-CH3 -phenyl                        169 (cPr)2 CH 2-Cl-4-CN-phenyl  170 phenyl(cPr)CH 2-Cl-4-CN-phenyl  171 2-furanyl(cPr)CH 2-Cl-4-CN-phenyl  172 3-furan(cPr)CH 2-Cl-4-CN-phenyl  173 2-thienyl(cPr)CH 2-Cl-4-CN-phenyl  174 3-thienyl(cPr)CH 2-Cl-4-CN-phenyl  175 2-isoxazolyl(cPr)CH 2-Cl-4-CN-phenyl  176 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-CN-phenyl  177 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-CN-phenyl  178 cPr-CH(CH3) 2-Cl-4-CN-phenyl  179 1-cPr-CH(CH2 CH3) 2-Cl-4-CN-phenyl  180 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-CN-phenyl  181 1-cPr-CH(CH2 OCH3) 2-Cl-4-CN-phenyl  182 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-CN-phenyl  183 (cBu)2 CH 2-Cl-4-CN-phenyl  184 phenyl(cBu)CH 2-Cl-4-CN-phenyl  185 2-furanyl(cBu)CH 2-Cl-4-CN-phenyl  186 3-furan(cBu)CH 2-Cl-4-CN-phenyl  187 2-thienyl(cBu)CH 2-Cl-4-CN-phenyl  188 3-thienyl(cBu)CH 2-Cl-4-CN-phenyl  189 2-isoxazolyl(cBu)CH 2-Cl-4-CN-phenyl  190 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-CN-phenyl  191 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-CN-phenyl  192 cBu-CH(CH3) 2-Cl-4-CN-phenyl  193 1-cBu-CH(CH2 CH3) 2-Cl-4-CN-phenyl  194 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-CN-phenyl  195 1-cBu-CH(CH2 OCH3) 2-Cl-4-CN-phenyl  196 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-CN-phenyl  197 (cPr)2 CH 2-CF3 -4-Cl-phenyl  198 phenyl(cPr)CH 2-CF3 -4-Cl-phenyl  199 2-furanyl(cPr)CH 2-CF3 -4-Cl-phenyl  200 3-furan(cPr)CH 2-CF3 -4-Cl-phenyl  201 2-thienyl(cPr)CH 2-CF3 -4-Cl-phenyl  202 3-thienyl(cPr)CH 2-CF3 -4-Cl-phenyl  203 2-isoxazolyl(cPr)CH 2-CF3 -4-Cl-pheny1  204 2-(5-CH3 -furanyl)(cPr)CH 2-CF3 -4-Cl-phenyl  205 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CF3 -4-Cl-phenyl  206 cPr-CH(CH3) 2-CF3 -4-Cl-phenyl  207 1-cPr-CH(CH2 CH3) 2-CF3 -4-Cl-phenyl  208 1-cPr-CH(CH2 CH2 CH3) 2-CF3 -4-Cl-phenyl                        209 1-cPr-CH(CH2 OCH3) 2-CF3                       -4-Cl-phenyl  210 1-cPr-CH(CH2 CH2 OCH3) 2-CF3 -4-Cl-phenyl                        211 (cBu)2 CH 2-CF3 -4-Cl-phenyl                        212 phenyl(cBu)CH 2-CF3 -4-Cl-phenyl                        213 2-furanyl(cBu)CH 2-CF3 -4-Cl-phenyl  214 3-furan(cBu)CH 2-CF3 -4-Cl-phenyl  215 2-thienyl(cBu)CH 2-CF3 -4-Cl-phenyl  216 3-thienyl(cBu)CH 2-CF3 -4-Cl-phenyl  217 2-isoxazolyl(cBu)CH 2-CF3 -4-Cl-phenyl  218 2-(5-CH3 -furanyl)(cBu)CH 2-CF3 -4-Cl-phenyl  219 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CF3 -4-Cl-phenyl  220 cBu-CH(CH3) 2-CF3 -4-Cl-phenyl  221 1-cBu-CH(CH2 CH3) 2-CF3 -4-Cl-phenyl  222 1-cBu-CH(CH2 CH2 CH3) 2-CF3 -4-Cl-phenyl                        223 1-cBu-CH(CH2 OCH3) 2-CF3                       -4-Cl-phenyl  224 1-cBu-CH(CH2 CH2 OCH3) 2-CF3 -4-Cl-phenyl                        225 (cPr)2 CH 2-CF3 -4-MeO-phenyl                        226 phenyl(cPr)CH 2-CF3 -4-MeO-phenyl                        227 2-furanyl(cPr)CH 2-CF3 -4-MeO-phenyl  228 3-furan(cPr)CH 2-CF3 -4-MeO-phenyl  229 2-thienyl(cPr)CH 2-CF3 -4-MeO-phenyl  230 3-thienyl(cPr)CH 2-CF3 -4-MeO-phenyl  231 2-isoxazolyl(cPr)CH 2-CF3 -4-MeO-phenyl  232 2-(5-CH3 -furanyl)(cPr)CH 2-CF3 -4-MeO-phenyl  233 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CF3 -4-MeO-phenyl  234 cPr-CH(CH3) 2-CF3 -4-MeO-phenyl  235 1-cPr-CH(CH2 CH3) 2-CF3 -4-MeO-phenyl  236 1-cPr-CH(CH2 CH2 CH3) 2-CF3 -4-MeO-phenyl                        237 1-cPr-CH(CH2 OCH3) 2-CF3                       -4-MeO-phenyl  238 1-cPr-CH(CH2 CH2 OCH3) 2-CF3 -4-MeO-phenyl                        239 (cBu)2 CH 2-CF3 -4-MeO-phenyl                        240 phenyl(cBu)CH 2-CF3 -4-MeO-phenyl                        241 2-furanyl(cBu)CH 2-CF3 -4-MeO-phenyl  242 3-furan(cBu)CH 2-CF3 -4-MeO-phenyl  243 2-thienyl(cBu)CH 2-CF3 -4-MeO-phenyl  244 3-thienyl(cBu)CH 2-CF3 -4-MeO-phenyl  245 2-isoxazolyl(cBu)CH 2-CF3 -4-MeO-phenyl  246 2-(5-CH3 -furanyl)(cBu)CH 2-CF3 -4-MeO-phenyl  247 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CF3 -4-MeO-phenyl  248 cBu-CH(CH3) 2-CF3 -4-MeO-phenyl  249 1-cBu-CH(CH2 CH3) 2-CF3 -4-MeO-phenyl  250 1-cBu-CH(CH2 CH2 CH3) 2-CF3 -4-MeO-phenyl                        251 1-cBu-CH(CH2 OCH3) 2-CF3                       -4-MeO-phenyl  252 1-cBu-CH(CH2 CH2 OCH3) 2-CF3 -4-MeO-phenyl                        253 (cPr)2 CH 2-CF3 -4-n-PrO-phenyl  254 phenyl(cPr)CH 2-CF3 -4-n-PrO-phenyl  255 2-furanyl(cPr)CH 2-CF3 -4-n-PrO-phenyl  256 3-furan(cPr)CH 2-CF3 -4-n-PrO-phenyl  257 2-thienyl(cPr)CH 2-CF3 -4-n-PrO-phenyl  258 3-thienyl(cPr)CH 2-CF3 -4-n-PrO-phenyl  259 2-isoxazolyl(cPr)CH 2-CF3 -4-n-PrO-phenyl  260 2-(5-CH3 -furanyl)(cPr)CH 2-CF3 -4-n-PrO-phenyl  261 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CF3 -4-n-PrO-phenyl                        262 cPr-CH(CH3) 2-CF3 -4-n-PrO-phen                       yl  263 1-cPr-CH(CH2 CH3) 2-CF3 -4-n-PrO-phenyl  264 1-cPr-CH(CH2 CH2 CH3) 2-CF3 -4-n-PrO-phenyl                        265 1-cPr-CH(CH2 OCH3) 2-CF3                       -4-n-PrO-phenyl  266 1-cPr-CH(CH2 CH2 OCH3) 2-CF3 -4-n-PrO-phenyl                        267 (cBu)2 CH 2-CF3 -4-n-PrO-phenyl  268 phenyl(cBu)CH 2-CF3 -4-n-PrO-phenyl  269 2-furanyl(cBu)CH 2-CF3 -4-n-PrO-phenyl  270 3-furan(cBu)CH 2-CF3 -4-n-PrO-phenyl  271 2-thienyl(cBu)CH 2-CF3 -4-n-PrO-phenyl  272 3-thienyl(cBu)CH 2-CF3 -4-n-PrO-phenyl  273 2-isoxazolyl(cBu)CH 2-CF3 -4-n-PrO-phenyl  274 2-(5-CH3 -furanyl)(cBu)CH 2-CF3 -4-n-PrO-phenyl  275 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CF3 -4-n-PrO-phenyl                        276 cBu-CH(CH3) 2-CF3 -4-n-PrO-phen                       yl  277 1-cBu-CH(CH2 CH3) 2-CF3 -4-n-PrO-phenyl  278 1-cBu-CH(CH2 CH2 CH3) 2-CF3 -4-n-PrO-phenyl                        279 1-cBu-CH(CH2 OCH3) 2-CF3                       -4-n-PrO-phenyl  280 1-cBu-CH(CH2 CH2 OCH3) 2-CF3 -4-n-PrO-phenyl                        281 (cPr)2 CH 2,4-diCF3 -phenyl                        282 phenyl(cPr)CH 2,4-diCF3 -phenyl                        283 2-furanyl(cPr)CH 2,4-diCF3 -phenyl                        284 3-furan(cPr)CH 2,4-diCF3 -phenyl                        285 2-thienyl(cPr)CH 2,4-diCF3 -phenyl                        286 3-thienyl(cPr)CH 2,4-diCF3 -phenyl                        287 2-isoxazolyl(cPr)CH 2,4-diCF3                       -phenyl  288 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCF3 -phenyl  289 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCF3 -phenyl  290 cPr-CH(CH3) 2,4-diCF3 -phenyl  291 1-cPr-CH(CH2 CH3) 2,4-diCF3 -phenyl  292 1-cPr-CH(CH2 CH2 CH3) 2,4-diCF3 -phenyl                        293 1-cPr-CH(CH2 OCH3) 2,4-diCF.sub                       .3 -phenyl  294 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCF3 -phenyl                        295 (cBu)2 CH 2,4-diCF3 -phenyl                        296 phenyl(cBu)CH 2,4-diCF3 -phenyl                        297 2-furanyl(cBu)CH 2,4-diCF3 -phenyl                        298 3-furan(cBu)CH 2,4-diCF3 -phenyl                        299 2-thienyl(cBu)CH 2,4-diCF3 -phenyl                        300 3-thienyl(cBu)CH 2,4-dieF3-phenyl                        301 2-isoxazolyl(cBu)CH 2,4-diCF3                       -phenyl  302 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCF3 -phenyl  303 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCF3 -phenyl  304 cBu-CH(CH3) 2,4-diCF3 -phenyl  305 1-cBu-CH(CH2 CH3) 2,4-diCF3 -phenyl  306 1-cBu-CH(CH2 CH2 CH3) 2,4-diCF3 -phenyl                        307 1-cBu-CH(CH2 OCH3) 2,4-diCF.sub                       .3 -phenyl  308 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCF3 -phenyl                        309 (cPr)2 CH 2-CF3 -4-F-phenyl                        310 phenyl(cPr)CH 2-CF3 -4-F-phenyl                        311 2-furanyl(cPr)CH 2-CF3 -4-F-phenyl                        312 3-furan(cPr)CH 2-CF3 -4-F-phenyl                        313 2-thienyl(cPr)CH 2-CF3 -4-F-phenyl                        314 3-thienyl(cPr)CH 2-CF3 -4-F-phenyl                        315 2-isoxazolyl(cPr)CH 2-CF3 -4-F-pheny                       l  316 2-(5-CH3 -furanyl)(cPr)CH 2-CF3 -4-F-phenyl  317 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CF3 -4-F-phenyl  318 cPr-CH(CH3) 2-CF3 -4-F-phenyl  319 1-cPr-CH(CH2 CH3) 2-CF3 -4-F-phenyl  320 1-cPr-CH(CH2 CH2 CH3) 2-CF3 -4-F-phenyl                        321 1-cPr-CH(CH2 OCH3) 2-CF3                       -4-F-phenyl  322 1-cPr-CH(CH2 CH2 OCH3) 2-CF3 -4-F-phenyl                        323 (cBu)2 CH 2-CF3 -4-F-phenyl                        324 phenyl(cBu)CH 2-CF3 -4-F-phenyl                        325 2-furanyl(cBu)CH 2-CF3 -4-F-phenyl                        326 3-furan(cBu)CH 2-CF3 -4-F-phenyl                        327 2-thienyl(cBu)CH 2-CF3 -4-F-phenyl                        328 3-thienyl(cBu)CH 2-CF3 -4-F-phenyl                        329 2-isoxazolyl(cBu)CH 2-CF3 -4-F-pheny                       l  330 2-(5-CH3 -furanyl)(cBu)CH 2-CF3 -4-F-phenyl  331 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CF3 -4-F-phenyl  332 cBu-CH(CH3) 2-CF3 -4-F-phenyl  333 1-cBu-CH(CH2 CH3) 2-CF3 -4-F-phenyl  334 1-cBu-CH(CH2 CH2 CH3) 2-CF3 -4-F-phenyl                        335 1-cBu-CH(CH2 OCH3) 2-CF3                       -4-F-phenyl  336 1-cBu-CH(CH2 CH2 OCH3) 2-CF3 -4-F-phenyl                        337 (cPr)2 CH 2-CH3 -4-Cl-pheriyl                        338 phenyl(cPr)CH 2-CH3 -4-Cl-phenyl                        339 2-furanyl(cPr)CH 2-CH3 -4-Cl-phenyl  340 3-furan(cPr)CH 2-CH3 -4-Cl-phenyl  341 2-thienyl(cPr)CH 2-CH3 -4-Cl-phenyl  342 3-thienyl(cPr)CH 2-CH3 -4-Cl-phenyl  343 2-isoxazolyl(cPr)CH 2-CH3 -4-Cl-phenyl  344 2-(5-CH3 -furanyl)(cPr)CH 2-CH3 -4-Cl-phenyl  345 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CH3 -4-Cl-phenyl  346 cPr-CH(CH3) 2-CH3 -4-Cl-phenyl  347 1-cPr-CH(CH2 CH3) 2-CH3 -4-Cl-phenyl  348 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -4-Cl-phenyl                        349 1-cPr-CH(CH2 OCH3) 2-CH3                       -4-Cl-phenyl  350 1-cPr-CH(CH2 CH2 OCH3) 2-CH3 -4-Cl-phenyl                        351 (cBu)2 CH 2-CH3 -4-Cl-phenyl                        352 phenyl(cBu)CH 2-CH3 -4-Cl-phenyl                        353 2-furanyl(cBu)CH 2-CH3 -4-Cl-phenyl  354 3-furan(cBu)CH 2-CH3 -4-Cl-phenyl  355 2-thienyl(cBu)CH 2-CH3 -4-Cl-phenyl  356 3-thienyl(cBu)CH 2-CH3 -4-Cl-phenyl  357 2-isoxazolyl(cBu)CH 2-CH3 -4-Cl-phenyl  358 2-(5-CH3 -furanyl)(cBu)CH 2-CH3 -4-Cl-phenyl  359 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CH3 -4-Cl-phenyl  360 cBu-CH(CH3) 2-CH3 -4-Cl-phenyl  361 1-cBu-CH(CH2 CH3) 2-CH3 -4-Cl-phenyl  362 1-cBu-CH(CH2 CH2 CH3) 2-CH3 -4-Cl-phenyl                        363 1-cBu-CH(CH2 OCH3) 2-CH3                       -4-Cl-phenyl  364 1-cBu-CH(CH2 CH2 OCH3) 2-CH3 -4-Cl-phenyl                        365 (cPr)2 CH 2-CH3 -4-MeO-phenyl                        366 phenyl(cPr)CH 2-CH3 -4-MeO-phenyl                        367 2-furanyl(cPr)CH 2-CH3 -4-MeO-phenyl  368 3-furan(cPr)CH 2-CH3 -4-MeO-phenyl  369 2-thienyl(cPr)CH 2-CH3 -4-MeO-phenyl  370 3-thienyl(cPr)CH 2-CH3 -4-MeO-phenyl  371 2-isoxazolyl(cPr)CH 2-CH3 -4-MeO-phenyl  372 2-(5-CH3 -furanyl)(cPr)CH 2-CH3 -4-MeO-phenyl  373 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CH3 -4-MeO-phenyl  374 cPr-CH(CH3) 2-CH3 -4-MeO-phenyl  375 1-cPr-CH(CH2 CH3) 2-CH3 -4-MeO-phenyl  376 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-phenyl                        377 1-cPr-CH(CH2 OCH3) 2-CH3                       -4-MeO-phenyl  378 1-cPr-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-phenyl                        379 (cBu)2 CH 2-CH3 -4-MeO-phenyl                        380 phenyl(cBu)CH 2-CH3 -4-MeO-phenyl                        381 2-furanyl(cBu)CH 2-CH3 -4-MeO-phenyl  382 3-furan(cBu)CH 2-CH3 -4-MeO-phenyl  383 2-thienyl(cBu)CH 2-CH3 -4-MeO-phenyl  384 3-thienyl(cBu)CH 2-CH3 -4-MeO-phenyl  385 2-isoxazolyl(cBu)CH 2-CH3 -4-MeO-phenyl  386 2-(5-CH3 -furanyl)(cBu)CH 2-CH3 -4-MeO-phenyl  387 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CH3 -4-MeO-phenyl  388 cBu-CH(CH3) 2-CH3 -4-MeO-phenyl  389 1-cBu-CH(CH2 CH3) 2-CH3 -4-MeO-phenyl  390 1-cBu-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-phenyl                        391 1-cBu-CH(CH2 OCH3) 2-CH3                       -4-MeO-phenyl  392 1-cBu-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-phenyl                        393 (cPr)2 CH 2,4-diCH3 -phenyl                        394 phenyl(cPr)CH 2,4-diCH3 -phenyl                        395 2-furanyl(cPr)CH 2,4-diCH3 -phenyl                        396 3-furan(cPr)CH 2,4-diCH3 -phenyl                        397 2-thienyl(cPr)CH 2,4-diCH3 -phenyl                        398 3-thienyl(cPr)CH 2,4-diCH3 -phenyl                        399 2-isoxazolyl(cPr)CH 2,4-diCH3                       -phenyl  400 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCH3 -phenyl  401 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCH3 -phenyl  402 cPr-CH(CH3) 2,4-diCH3 -phenyl  403 1-cPr-CH(CH2 CH3) 2,4-diCH3 -phenyl  404 1-cPr-CH(CH2 CH2 CH3) 2,4-diCH3 -phenyl                        405 1-cPr-CH(CH2 OCH3) 2,4-diCH.sub                       .3 -phenyl  406 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCH3 -phenyl                        407 (cBu)2 CH 2,4-diCH3 -phenyl                        408 phenyl(cBu)CH 2,4-diCH3 -phenyl                        409 2-furanyl(cBu)CH 2,4-diCH3 -phenyl                        410 3-furan(cBu)CH 2,4-diCH3 -phenyl                        411 2-thienyl(cBu)CH 2,4-diCH3 -phenyl                        412 3-thienyl(cBu)CH 2,4-diCH3 -phenyl                        413 2-isoxazolyl(cBu)CH 2,4-diCH3                       -phenyl  414 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCH3 -phenyl  415 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCH3 -phenyl  416 cBu-CH(CH3) 2,4-diCH3 -phenyl  417 1-cBu-CH(CH2 CH3) 2,4-diCH3 -phenyl  418 1-cBu-CH(CH2 CH2 CH3) 2,4-diCH3 -phenyl                        419 1-cBu-CH(CH2 OCH3 2,4-diCH.sub.                       3 -phenyl  420 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCH3 -phenyl                        421 (cPr)2 CH 2-CH3 -4-(CH3).s                       ub.2 N-phenyl  422 phenyl(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl  423 2-furanyl(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl  424 3-furan(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl  425 2-thienyl(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl  426 3-thienyl(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl  427 2-isoxazolyl(cPr)CH 2-CH3 -4-(CH3)2 N-phenyl                        428 2-(5-CH3 -furanyl)(cPr)CH 2-CH3                        -4-(CH3)2 N-phenyl  429 2-(4-CH3 -isoxazolyl)(cPr)CH 2-CH3 -4-(CH3)2                       N-phenyl  430 cPr-CH(CH3) 2-CH3 -4-(CH3)2 N-phenyl  431 1-cPr-CH(CH2 CH3) 2-CH3 -4-(CH3)2 N-phenyl  432 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -4-(CH3)2                       N-phenyl  433 1-cPr-CH(CH2 OCH3) 2-CH3 -4-(CH3)2                       N-phenyl  434 1-cPr-CH(CH2 CH2 OCH3) 2-CH3 -4-(CH3)2                        N-phenyl  435 (cBu)2 CH 2-CH3 -4-(CH3)2 N-phenyl  436 phenyl(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl  437 2-furanyl(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl  438 3-furan(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl  439 2-thienyl(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl  440 3-thienyl(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl  441 2-isoxazolyl(cBu)CH 2-CH3 -4-(CH3)2 N-phenyl                        442 2-(5-CH3 -furanyl)(cBu)CH 2-CH3                        -4-(CH3)2 N-phenyl  443 2-(4-CH3 -isoxazolyl)(cBu)CH 2-CH3 -4-(CH3)2                       N-phenyl  444 cBu-CH(CH3) 2-CH3 -4-(CH3)2 N-phenyl  445 1-cBu-CH(CH2 CH3) 2-CH3 -4-(CH3)2 N-phenyl  446 1-cBu-CH(CH2 CH2 CH3) 2-CH3 -4-(CH3)2                       N-phenyl  447 1-cBu-CH(CH2 OCH3) 2-CH3 -4-(CH3)2                       N-phenyl  448 1-cBu-CH(CH2 CH2 OCH3) 2-CH3 -4-(CH3)2                        N-phenyl  449 (cPr)2 CH 2-MeO-4-CH3 -phenyl  450 phenyl(cPr)CH 2-MeO-4-CH3 -phenyl  451 2-furanyl(cPr)CH 2-MeO-4-CH3 -phenyl  452 3-furan(cPr)CH 2-MeO-4-CH3 -phenyl  453 2-thienyl(cPr)CH 2-MeO-4-CH3 -phenyl  454 3-thienyl(cPr)CH 2-MeO-4-CH3 -phenyl  455 2-isoxazolyl(cPr)CH 2-MeO-4-CH3 -phenyl  456 2-(5-CH3 -furanyl)(cPr)CH 2-MeO-4-CH3 -phenyl  457 2-(4-CH3 -isoxazolyl)(cPr)CH 2-MeO-4-CH3 -phenyl  458 cPr-CH(CH3) 2-MeO-4-CH3 -phenyl  459 1-cPr-CH(CH2 CH3) 2-MeO-4-CH3 -phenyl  460 1-cPr-CH(CH2 CH2 CH3) 2-MeO-4-CH3 -phenyl                        461 1-cPr-CH(CH2 OCH3) 2-MeO-4-CH.s                       ub.3 -phenyl  462 1-cPr-CH(CH2 CH2 OCH3) 2-MeO-4-CH3 -phenyl                        463 (cBu)2 CH 2-MeO-4-CH3 -phenyl                        464 phenyl(cBu)CH 2-MeO-4-CH3 -phenyl                        465 2-furanyl(cBu)CH 2-MeO-4-CH3                       -phenyl  466 3-furan(cBu)CH 2-MeO-4-CH3 -phenyl  467 2-thienyl(cBu)CH 2-MeO-4-CH3 -phenyl  468 3-thienyl(cBu)CH 2-MeO-4-CH3 -phenyl  469 2-isoxazolyl(cBu)CH 2-MeO-4-CH3 -phenyl  470 2-(5-CH3 -furanyl)(cBu)CH 2-MeO-4-CH3 -phenyl  471 2-(4-CH3 -isoxazolyl)(cBu)CH 2-MeO-4-CH3 -phenyl  472 cBu-CH(CH3) 2-MeO-4-CH3 -phenyl  473 1-cBu-CH(CH2 CH3) 2-MeO-4-CH3 -phenyl  474 1-cBu-CH(CH2 CH2 CH3) 2-MeO-4-CH3 -phenyl                        475 1-cBu-CH(CH2 OCH3) 2-MeO-4-CH.s                       ub.3 -phenyl  476 1-cBu-CH(CH2 CH2 OCH3) 2-MeO-4-CH3 -phenyl                        477 (cPr)2 CH 2-MeO-4-CF3 -phenyl                        478 phenyl(cPr)CH 2-MeO-4-CF3 -phenyl                        479 2-furanyl(cPr)CH 2-MeO-4-CF3                       -phenyl  480 3-furan(cPr)CH 2-MeO-4-CF3 -phenyl  481 2-thienyl(cPr)CH 2-MeO-4-CF3 -phenyl  482 3-thienyl(cPr)CH 2-MeO-4-CF3 -phenyl  483 2-isoxazolyl(cPr)CH 2-MeO-4-CF3 -phenyl  484 2-(5-CH3 -furanyl)(cPr)CH 2-MeO-4-CF3 -phenyl  485 2-(4-CH3 -isoxazolyl)(cPr)CH 2-MeO-4-CF3 -phenyl  486 cPr-CH(CH3) 2-MeO-4-CF3 -phenyl  487 1-cPr-CH(CH2 CH3) 2-MeO-4-CF3 -phenyl  488 1-cPr-CH(CH2 CH2 CH3) 2-MeO-4-CF3 -phenyl                        489 1-cPr-CH(CH2 OCH3) 2-MeO-4-CF.s                       ub.3 -phenyl  490 1-cPr-CH(CH2 CH2 OCH3) 2-MeO-4-CF3 -phenyl                        491 (cBu)2 CH 2-MeO-4-CF3 -phenyl                        492 phenyl(cBu)CH 2-MeO-4-CF3 -phenyl                        493 2-furanyl(cBu)CH 2-MeO-4-CF3                       -phenyl  494 3-furan(cBu)CH 2-MeO-4-CF3 -phenyl  495 2-thienyl(cBu)CH 2-MeO-4-CF3 -phenyl  496 3-thienyl(cBu)CH 2-MeO-4-CF3 -phenyl  497 2-isoxazolyl(cBu)CH 2-MeO-4-CF3 -phenyl  498 2-(5-CH3 -furanyl)(cBu)CH 2-MeO-4-CF3 -phenyl  499 2-(4-CH3 -isoxazolyl)(cBu)CH 2-MeO-4-CF3 -phenyl  500 cBu-CH(CH3) 2-MeO-4-CF3 -phenyl  501 1-cBu-CH(CH2 CH3) 2-MeO-4-CF3 -phenyl  502 1-cBu-CH(CH2 CH2 CH3) 2-MeO-4-CF3 -phenyl                        503 1-cBu-CH(CH2 OCH3) 2-MeO-4-CF.s                       ub.3 -phenyl  504 1-cBu-CH(CH2 CH2 OCH3) 2-MeO-4-CF3 -phenyl                        505 (cPr)2 CH 2-MeO-4-Cl-phenyl                        506 phenyl(cPr)CH 2-MeO-4-Cl-phenyl  507 2-furanyl(cPr)CH 2-MeO-4-Cl-phenyl  508 3-furan(cPr)CH 2-MeO-4-Cl-phenyl  509 2-thienyl(cPr)CH 2-MeO-4-Cl-phenyl  510 3-thienyl(cPr)CH 2-MeO-4-Cl-phenyl  511 2-isoxazolyl(cPr)CH 2-MeO-4-Cl-phenyl  512 2-(5-CH3 -furanyl)(cPr)CH 2-MeO-4-Cl-phenyl  513 2-(4-CH3 -isoxazolyl)(cPr)CH 2-MeO-4-Cl-phenyl  514 cPr-CH(CH3) 2-MeO-4-Cl-phenyl  515 1-cPr-CH(CH2 CH3) 2-MeO-4-Cl-phenyl  516 1-cPr-CH(CH2 CH2 CH3) 2-MeO-4-Cl-phenyl  517 1-cPr-CH(CH2 OCH3) 2-MeO-4-Cl-phenyl  518 1-cPr-CH(CH2 CH2 OCH3) 2-MeO-4-Cl-phenyl  519 (cBu)2 CH 2-MeO-4-Cl-phenyl  520 phenyl(cBu)CH 2-MeO-4-Cl-phenyl  521 2-furanyl(cBu)CH 2-MeO-4-Cl-phenyl  522 3-furan(cBu)CH 2-MeO-4-Cl-phenyl  523 2-thienyl(cBu)CH 2-MeO-4-Cl-phenyl  524 3-thienyl(cBu)CH 2-MeO-4-Cl-phenyl  525 2-isoxazolyl(cBu)CH 2-MeO-4-Cl-phenyl  526 2-(5-CH3 -furanyl)(cBu)CH 2-MeO-4-Cl-phenyl  527 2-(4-CH3 -isoxazolyl)(cBu)CH 2-MeO-4-Cl-phenyl  528 cBu-CH(CH3) 2-MeO-4-Cl-phenyl  529 1-cBu-CH(CH2 CH3) 2-MeO-4-Cl-phenyl  530 1-cBu-CH(CH2 CH2 CH3) 2-MeO-4-Cl-phenyl  531 1-cBu-CH(CH2 OCH3) 2-MeO-4-Cl-phenyl  532 1-cBu-CH(CH2 CH2 OCH3) 2-MeO-4-Cl-phenyl  533 (cPr)2 CH 2,4-diMeO-phenyl  534 phenyl(cPr)CH 2,4-diMeO-phenyl  535 2-furanyl(cPr)CH 2,4-diMeO-phenyl  536 3-furan(cPr)CH 2,4-diMeO-phenyl  537 2-thienyl(cPr)CH 2,4-diMeO-phenyl  538 3-thienyl(cPr)CH 2,4-diMeO-phenyl  539 2-isoxazolyl(cPr)CH 2,4-diMeO-phenyl  540 2-(5-CH3 -furanyl)(cPr)CH 2,4-diMeO-phenyl  541 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diMeO-phenyl  542 cPr-CH(CH3) 2,4-diMeO-phenyl  543 1-cPr-CH(CH2 CH3) 2,4-diMeO-phenyl  544 1-cPr-CH(CH2 CH2 CH3) 2,4-diMeO-phenyl  545 1-cPr-CH(CH2 OCH3) 2,4-diMeO-phenyl  546 1-cPr-CH(CH2 CH2 OCH3) 2,4-diMeO-phenyl  547 (cBu)2 CH 2,4-diMeO-phenyl  548 phenyl(cBu)CH 2,4-diMeO-phenyl  549 2-furanyl(cBu)CH 2,4-diMeO-phenyl  550 3-furan(cBu)CH 2,4-diMeO-phenyl  551 2-thienyl(cBu)CH 2,4-diMeO-phenyl  552 3-thienyl(cBu)CH 2,4-diMeO-phenyl  553 2-isoxazolyl(cBu)CH 2,4-diMeO-phenyl  554 2-(5-CH3 -furanyl)(cBu)CH 2,4-diMeO-phenyl  555 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diMeO-phenyl  556 cBu-CH(CH3) 2,4-diMeO-phenyl  557 1-cBu-CH(CH2 CH3) 2,4-diMeO-phenyl  558 1-cBu-CH(CH2 CH2 CH3) 2,4-diMeO-phenyl  559 1-cBu-CH(CH2 OCH3) 2,4-diMeO-phenyl  560 1-cBu-CH(CH2 CH2 OCH3) 2,4-diMeO-phenyl  561 (cPr)2 CH 2,4-diCl-6-CH3 -phenyl  562 phenyl(cPr)CH 2,4-diCl-6-CH3 -phenyl  563 2-furanyl(cPr)CH 2,4-diCl-6-CH3 -phenyl  564 3-furan(cPr)CH 2,4-diCl-6-CH3 -phenyl  565 2-thienyl(cPr)CH 2,4-diCl-6-CH3 -phenyl  566 3-thienyl(cPr)CH 2,4-diCl-6-CH3 -phenyl  567 2-isoxazolyl(cPr)CH 2,4-diCl-6-CH3 -phenyl  568 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCl-6-CH3 -phenyl  569 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCl-6-CH3 -phenyl                        570 cPr-CH(CH3) 2,4-diCl-6-CH3                       -phenyl  571 1-CPr-CH(CH2 CH3) 2,4-diCl-6-CH3 -phenyl  572 1-cPr-CH(CH2 CH2 CH3) 2,4-diCl-6-CH3 -phenyl                        573 1-cPr-CH(CH2 OCH3) 2,4-diCl-6-C                       H3 -phenyl  574 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCl-6-CH3 -phenyl                        575 (cBu)2 CH 2,4-diCl-6-CH3                       -phenyl  576 phenyl(cBu)CH 2,4-diCl-6-CH3 -phenyl  577 2-furanyl(cBu)CH 2,4-diCl-6-CH3 -phenyl  578 3-furan(cBu)CH 2,4-diCl-6-CH3 -phenyl  579 2-thienyl(cBu)CH 2,4-diCl-6-CH3 -phenyl  580 3-thienyl(cBu)CH 2,4-diCl-6-CH3 -phenyl  581 2-isoxazolyl(cBu)CH 2,4-diCl-6-CH3 -phenyl  582 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCl-6-CH3 -phenyl  583 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCl-6-CH3 -phenyl                        584 cBu-CH(CH3) 2,4-diCl-6-CH3                       -phenyl  585 1-cBu-CH(CH2 CH3) 2,4-diCl-6-CH3 -phenyl  586 1-cBu-CH(CH2 CH2 CH3) 2,4-diCl-6-CH3 -phenyl                        587 1-cBu-CH(CH2 OCH3) 2,4-diCl-6-C                       H3 -phenyl  588 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCl-6-CH3 -phenyl                        589 (cPr)2 CH 2,4-diCl-5-F-phenyl                        590 phenyl(cPr)CH 2,4-diCl-5-F-phenyl                        591 2-furanyl(cPr)CH 2,4-diCl-5-F-phenyl                        592 3-furan(cPr)CH 2,4-diCl-5-F-phenyl                        593 2-thienyl(cPr)CH 2,4-diCl-5-F-phenyl                        594 3-thienyl(cPr)CH 2,4-diCl-5-F-phenyl                        595 2-isoxazolyl(cPr)CH 2,4-diCl-5-F-phenyl                        596 2-(5-CH3 -furanyl(cPr)CH 2,4-diCl-5-                       F-phenyl  597 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCl-5-F-phenyl  598 cPr-CH(CH3) 2,4-diCl-5-F-phenyl  599 1-cPr-CH(CH2 CH3) 2,4-diCl-5-F-phenyl  600 1-CPr-CH(CH2 CH2 CH3) 2,4-diCl-5-F-phenyl  601 1-cPr-CH(CH2 OCH3) 2,4-diCl-5-F-phenyl  602 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCl-5-F-phenyl  603 (cBu)2 CH 2,4-diCl-5-F-phenyl  604 phenyl(cBu)CH 2,4-diCl-5-F-phenyl  605 2-furanyl(cBu)CH 2,4-diCl-5-F-phenyl  606 3-furan(cBu)CH 2,4-diCl-5-F-phenyl  607 2-thienyl(cBu)CH 2,4-diCl-5-F-phenyl  608 3-thienyl(cBu)CH 2,4-diCl-5-F-phenyl  609 2-isoxazolyl(cBu)CH 2,4-diCl-5-F-phenyl  610 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCl-5-F-phenyl  611 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCl-5-F-phenyl  612 cBu-CH(CH3) 2,4-diCl-5-F-phenyl  613 1-cBu-CH(CH2 CH3) 2,4-diCl-5-F-phenyl  614 1-cBu-CH(CH2 CH2 CH3) 2,4-diCl-5-F-phenyl  615 1-cBu-CH(CH2 OCH3) 2,4-diCl-5-F-phenyl  616 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCl-5-F-phenyl  617 (cPr)2 CH 2,4-diCl-6-MeS-phenyl  618 phenyl(cPr)CH 2,4-diCl-6-MeS-phenyl  619 2-furanyl(cPr)CH 2,4-diCl-6-MeS-phenyl  620 3-furan(cPr)CH 2,4-diCl-6-MeS-phenyl  621 2-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl  622 3-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl  623 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeS-phenyl  624 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCl-6-MeS-phenyl  625 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCl-6-MeS-phenyl  626 cPr-CH(CH3) 2,4-diCl-6-MeS-phenyl  627 1-cPr-CH(CH2 CH3) 2,4-diCl-6-MeS-phenyl  628 1-cPr-CH(CH2 CH2 CH3) 2,4-diCl-6-MeS-phenyl  629 1-cPr-CH(CH2 OCH3) 2,4-diCl-6-MeS-phenyl  630 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCl-6-MeS-phenyl                        631 (cBu)2 CH 2,4-diCl-6-MeS-phenyl                        632 phenyl(cBu)CH 2,4-diCl-6-MeS-phenyl                        633 2-furanyl(cBu)CH 2,4-diCl-6-MeS-phenyl                        634 3-furan(cBu)CH 2,4-diCl-6-MeS-phenyl                        635 2-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl                        636 3-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl                        637 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeS-phenyl  638 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCl-6-MeS-phenyl  639 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCl-6-MeS-phenyl  640 cBu-CH(CH3) 2,4-diCl-6-MeS-phenyl  641 1-cBu-CH(CH2 CH3) 2,4-diCl-6-MeS-phenyl  642 1-cBu-CH(CH2 CH2 CH3) 2,4-diCl-6-MeS-phenyl  643 1-cBu-CH(CH2 OCH3) 2,4-diCl-6-MeS-phenyl  644 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCl-6-MeS-phenyl                        645 (cPr)2 CH 2,4-diCl-6-MeO-phenyl                        646 phenyl(cPr)CH 2,4-diCl-6-MeO-phenyl                        647 2-furanyl(cPr)CH 2,4-diCl-6-MeO-phenyl                        648 3-furan(cPr)CH 2,4-diCl-6-MeO-phenyl                        649 2-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl                        650 3-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl                        651 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeO-phenyl  652 2-(5-CH3 -furanyl)(cPr)CH 2,4-diCl-6-MeO-phenyl  653 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4-diCl-6-MeO-phenyl  654 cPr-CH(CH3) 2,4-diCl-6-MeO-phenyl  655 1-cPr-CH(CH2 CH3) 2,4-diCl-6-MeO-phenyl  656 1-cPr-CH(CH2 CH2 CH3) 2,4-diCl-6-MeO-phenyl  657 1-cPr-CH(CH2 OCH3) 2,4-diCl-6-MeO-phenyl  658 1-cPr-CH(CH2 CH2 OCH3) 2,4-diCl-6-MeO-phenyl                        659 (cBu)2 CH 2,4-diCl-6-MeO-phenyl                        660 phenyl(cBu)CH 2,4-diCl-6-MeO-phenyl                        661 2-furanyl(cBu)CH 2,4-diCl-6-MeO-phenyl                        662 3-furan(cBu)CH 2,4-diCl-6-MeO-phenyl                        663 2-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl                        664 3-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl                        665 2-isaxazolyl(cBu)CH 2,4-diCl-6-MeO-phenyl  666 2-(5-CH3 -furanyl)(cBu)CH 2,4-diCl-6-MeO-phenyl  667 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4-diCl-6-MeO-phenyl  668 cBu-CH(CH3) 2,4-diCl-6-MeO-phenyl  669 1-cBu-CH(CH2 CH3) 2,4-diCl-6-MeO-phenyl  670 1-cBu-CH(CH2 CH2 CH3) 2,4-diCl-6-MeO-phenyl  671 1-cBu-CH(CH2 OCH3) 2,4-diCl-6-MeO-phenyl  672 1-cBu-CH(CH2 CH2 OCH3) 2,4-diCl-6-MeO-phenyl                        673 (cPr)2 CH 2,5-diCl-4-MeO-phenyl                        674 phenyl(cPr)CH 2,5-diCl-4-MeO-phenyl                        675 2-furanyl(cPr)CH 2,5-diCl-4-MeO-phenyl                        676 3-furan(cPr)CH 2,5-diCl-4-MeO-phenyl                        677 2-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl                        678 3-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl                        679 2-isoxazolyl(cPr)CH 2,5-diCl-4-MeO-phenyl  680 2-(5-CH3 -furanyl)(cPr)CH 2,5-diCl-4-MeO-phenyl  681 2-(4-CH3 -isoxazolyl)(cPr)CH 2,5-diCl-4-MeO-phenyl  682 cPr-CH(CH3) 2,5-diCl-4-MeO-phenyl  683 1-cPr-CH(CH2 CH3) 2,5-diCl-4-MeO-phenyl  684 1-cPr-CH(CH2 CH2 CH3) 2,5-diCl-4-MeO-phenyl  685 1-cPr-CH(CH2 OCH3) 2,5-diCl-4-MeO-phenyl  686 1-cPr-CH(CH2 CH2 OCH3) 2,5-diCl-4-MeO-phenyl                        687 (cBu)2 CH 2,5-diCl-4-MeO-phenyl                        688 phenyl(cBu)CH 2,5-diCl-4-MeO-phenyl                        689 2-furanyl(cBu)CH 2,5-diCl-4-MeO-phenyl                        690 3-furan(cBu)CH 2,5-diCl-4-MeO-phenyl                        691 2-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl                        692 3-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl                        693 2-isoxazolyl(cBu)CH 2,5-diCl-4-MeO-phenyl  694 2-(5-CH3 -furanyl)(cBu)CH 2,5-diCl-4-MeO-phenyl  695 2-(4-CH3 -isoxazolyl)(cBu)CH 2,5-diCl-4-MeO-phenyl  696 cBu-CH(CH3) 2,5-diCl-4-MeO-phenyl  697 1-cBu-CH(CH2 CH3) 2,5-diCl-4-MeO-phenyl  698 1-cBu-CH(CH2 CH2 CH3) 2,5-diCl-4-MeO-phenyl  699 1-cBu-CH(CH2 OCH3) 2,5-diCl-4-MeO-phenyl  700 1-cBu-CH(CH2 CH2 OCH3) 2,5-diCl-4-MeO-phenyl                        701 (cPr)2 CH 2,4,6-triCl-phenyl                        702 phenyl(cPr)CH 2,4,6-triCl-phenyl                        703 2-furanyl(cPr)CH 2,4,6-triCl-phenyl                        704 3-furan(cPr)CH 2,4,6-triCl-phenyl                        705 2-thienyl(cPr)CH 2,4,6-triCl-phenyl                        706 3-thienyl(cPr)CH 2,4,6-triCl-phenyl                        707 2-isoxazolyl(cPr)CH 2,4,6-triCl-phenyl                        708 2-(5-CH3 -furanyl)(cPr)CH 2,4,6-triC                       l-phenyl  709 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4,6-triCl-phenyl  710 cPr-CH(CH3) 2,4,6-triCl-phenyl  711 1-cPr-CH(CH2 CH3) 2,4,6-triCl-phenyl  712 1-cPr-CH(CH2 CH2 CH3) 2,4,6-triCl-phenyl  713 i-cPr-CH(CH2 OCH3) 2,4,6-triCl-phenyl  714 1-cPr-CH(CH2 CH2 OCH3) 2,4,6-triCl-phenyl  715 (cBu)2 CH 2,4,6-triCl-phenyl  716 phenyl(cBu)CH 2,4,6-triCl-phenyl  717 2-furanyl(cBu)CH 2,4,6-triCl-phenyl  718 3-furan(cBu)CH 2,4,6-triCl-phenyl  719 2-thienyl(cBu)CH 2,4,6-triCl-phenyl  720 3-thienyl(cBu)CH 2,4,6-triCl-phenyl  721 2-isoxazolyl(cBu)CH 2,4,6-triCl-phenyl  722 2-(5-CH3 -furanyl)(cBu)CH 2,4,6-triCl-phenyl  723 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4,6-triCl-phenyl  724 cBu-CH(CH3) 2,4,6-triCl-phenyl  725 1-cBu-CH(CH2 CH3) 2,4,6-triCl-phenyl  726 1-cBu-CH(CH2 CH2 CH3) 2,4,6-triCl-phenyl  727 1-cBu-CH(CH2 OCH3) 2,4,6-triCl-phenyl  728 1-cBu-CH(CH2 CH2 OCH3) 2,4,6-triCl-phenyl  729 (cPr)2 CH 2-Cl-4-CH3 -5-F-phenyl  730 phenyl(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  731 2-furanyl(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  732 3-furan(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  733 2-thienyl(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  734 3-thlenyl(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  735 2-isoxazolyl(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  736 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-CH3 -5-F-phenyl  737 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-CH3 -5-F-phenyl                        738 cPr-CH(CH3) 2-Cl-4-CH3                       -5-F-phenyl  739 1-cPr-CH(CH2 CH3) 2-Cl-4-CH3 -5-F-phenyl  740 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-CH3 -5-F-phenyl                        741 1-cPr-CH(CH2 OCH3) 2-Cl-4-CH.su                       b.3 -5-F-phenyl  742 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-CH3 -5-F-phenyl                        743 (cBu)2 CH 2-Cl-4-CH3 -5-F-pheny                       l  744 phenyl(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  745 2-furanyl(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  746 3-furan(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  747 2-thienyl(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  748 3-thienyl(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  749 2-isoxazolyl(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  750 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-CH3 -5-F-phenyl  751 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-CH3 -5-F-phenyl                        752 cBu-CH(CH3) 2-Cl-4-CH3                       -5-F-phenyl  753 1-cBu-CH(CH2 CH3) 2-Cl-4-CH3 -5-F-phenyl  754 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-CH3 -5-F-phenyl                        755 1-cBu-CH(CH2 OCH3) 2-Cl-4-CH.su                       b.3 -5-F-phenyl  756 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-CH3 -5-F-phenyl                        757 (cPr)2 CH 2-Cl-4-MeO-5-CH3                       -phenyl  758 phenyl(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  759 2-furanyl(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  760 3-furan(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  761 2-thienyl(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  762 3-thienyl(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  763 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl  764 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-MeO-5-CH3 -phenyl                        765 2-(4-CH3 -isoxazolyl)(cPr)CH                       2-Cl-4-MeO-5-CH3 -phenyl  766 cPr-CH(CH3) 2-Cl-4-MeO-5-CH3 -phenyl  767 1-cPr-CH(CH2 CH3) 2-Cl-4-MeO-5-CH3 -phenyl  768 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-MeO-5-CH3 -phenyl                        769 1-cPr-CH(CH2 OCH3) 2-Cl-4-MeO-5                       -CH3 -phenyl  770 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-MeO-5-CH3 -phenyl  771 (cBu)2 CH 2-Cl-4-MeO-5-CH3 -phenyl  772 phenyl(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  773 2-furanyl(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  774 3-furan(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  775 2-thienyl(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  776 3-thienyl(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  777 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl  778 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-MeO-5-CH3 -phenyl                        779 2-(4-CH3 -isoxazolyl)(cBu)CH                       2-Cl-4-MeO-5-CH3 -phenyl  780 cBu-CH(CH3) 2-Cl-4-MeO-5-CH3 -phenyl  781 1-cBu-CH(CH2 CH3) 2-Cl-4-MeO-5-CH3 -phenyl  782 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-MeO-5-CH3 -phenyl                        783 1-cBu-CH(CH2 OCH3) 2-Cl-4-MeO-5                       -CH3 -phenyl  784 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-MeO-5-CH3 -phenyl  785 (cPr)2 CH 2-Cl-4-MeO-5-F-phenyl  786 phenyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  787 2-furanyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  788 3-furan(cPr)CH 2-Cl-4-MeO-5-F-phenyl  789 2-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  790 3-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  791 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl  792 2-(5-CH3 -furanyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl  793 2-(4-CH3 -isoxazolyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl  794 cPr-CH(CH3) 2-Cl-4-MeO-5-F-phenyl  795 1-cPr-CH(CH2 CH3) 2-Cl-4-MeO-5-F-phenyl  796 1-cPr-CH(CH2 CH2 CH3) 2-Cl-4-MeO-5-F-phenyl  797 1-cPr-CH(CH2 OCH3) 2-Cl-4-MeO-5-F-phenyl  798 1-cPr-CH(CH2 CH2 OCH3) 2-Cl-4-MeO-5-F-phenyl                        799 (cBu)2 CH 2-Cl-4-MeO-5-F-phenyl                        800 phenyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                        801 2-furanyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                        802 3-furan(cBu)CH 2-Cl-4-MeO-5-F-phenyl                        803 2-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                        804 3-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                        805 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl  806 2-(5-CH3 -furanyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl  807 2-(4-CH3 -isoxazolyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl  808 cBu-CH(CH3) 2-Cl-4-MeO-5-F-phenyl  809 1-cBu-CH(CH2 CH3) 2-Cl-4-MeO-5-F-phenyl  810 1-cBu-CH(CH2 CH2 CH3) 2-Cl-4-MeO-5-F-phenyl  811 1-cBu-CH(CH2 OCH3) 2-Cl-4-MeO-5-F-phenyl  812 1-cBu-CH(CH2 CH2 OCH3) 2-Cl-4-MeO-5-F-phenyl                        813 (cPr)2 CH 2-CH3 -4-MeO-5-Cl-phe                       nyl  814 phenyl(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  815 2-furanyl(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  816 3-furan(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  817 2-thienyl(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  818 3-thienyl(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  819 2-isoxazolyl(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl  820 2-(5-CH3 -furanyl)(cPr)CH 2-CH3 -4-MeO-5-Cl-phenyl                        821 2-(4-CH3 -isoxazolyl)(cPr)CH                       2-CH3 -4-MeO-5-Cl-phenyl  822 cPr-CH(CH3) 2-CH3 -4-MeO-5-Cl-phenyl  823 1-cPr-CH(CH2 CH3) 2-CH3 -4-MeO-5-Cl-phenyl  824 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-5-Cl-phenyl                        825 1-cPr-CH(CH2 OCH3) 2-CH3                       -4-MeO-5-Cl-phenyl  826 1-cPr-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-5-Cl-phenyl  827 (cBu)2 CH 2-CH3 -4-MeO-5-Cl-phenyl  828 phenyl(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  829 2-furanyl(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  830 3-furan(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  831 2-thienyl(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  832 3-thienyl(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  833 2-isoxazolyl(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl  834 2-(5-CH3 -furanyl)(cBu)CH 2-CH3 -4-MeO-5-Cl-phenyl                        835 2-(4-CH3 -isoxazolyl)(cBu)CH                       2-CH3 -4-MeO-5-Cl-phenyl  836 cBu-CH(CH3) 2-CH3 -4-MeO-5-Cl-phenyl  837 1-cBu-CH(CH2 CH3) 2-CH3 -4-MeO-5-Cl-phenyl  838 1-cBu-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-5-Cl-phenyl                        839 1-cBu-CH(CH2 OCH3) 2-CH3                       -4-MeO-5-Cl-phenyl  840 1-cBu-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-5-Cl-phenyl  841 (cPr)2 CH 2,5-diCH3 -4-MeO-phenyl  842 phenyl(cPr)CH 2,5-diCH3 -4-MeO-phenyl  843 2-furanyl(cPr)CH 2,5-diCH3 -4-MeO-phenyl  844 3-furan(cPr)CH 2,5-diCH3 -4-MeO-phenyl  845 2-thienyl(cPr)CH 2,5-diCH3 -4-MeO-phenyl  846 3-thienyl(cPr)CH 2,5-diCH3 -4-MeO-phenyl  847 2-isoxazolyl(cPr)CH 2,5-diCH3 -4-MeO-phenyl  848 2-(5-CH3 -furanyl)(cPr)CH 2,5-diCH3 -4-MeO-phenyl                        849 2-(4-CH3 -isoxazolyl)(cPr)CH                       2,5-diCH3 -4-MeO-phenyl  850 cPr-CH(CH3) 2,5-diCH3 -4-MeO-phenyl  851 1-cPr-CH(CH2 CH3) 2,5-diCH3 -4-MeO-phenyl  852 1-cPr-CH(CH2 CH2 CH3) 2,5-diCH3 -4-MeO-phenyl                        853 1-cPr-CH(CH2 OCH3) 2,5-diCH.sub                       .3 -4-MeO-phenyl  854 1-cPr-CH(CH2 CH2 OCH3) 2,5-diCH3 -4-MeO-phenyl                        855 (cBu)2 CH 2,5-diCH3 -4-MeO-phen                       yl  856 phenyl(cBu)CH 2,5-diCH3 -4-MeO-phenyl  857 2-furanyl(cBu)CH 2,5-diCH3 -4-MeO-phenyl  858 3-furan(cBu)CH 2,5-diCH3 -4-MeO-phenyl  859 2-thienyl(cBu)CH 2,5-diCH3 -4-MeO-phenyl  860 3-thienyl(cBu)CH 2,5-diCH3 -4-MeO-phenyl  861 2-isdxazolyl(cBu)CH 2,5-diCH3 -4-MeO-phenyl  862 2-(5-CH3 -furanyl)(cBu)CH 2,5-diCH3 -4-MeO-phenyl                        863 2-(4-CH3 -isoxazolyl)(cBu)CH                       2,5-diCH3 -4-MeO-phenyl  864 cBu-CH(CH3) 2,5-diCH3 -4-MeO-phenyl  865 1-cBu-CH(CH2 CH3) 2,5-diCH3 -4-MeO-phenyl  866 1-cBu-CH(CH2 CH2 CH3) 2,5-diCH3 -4-MeO-phenyl                        867 1-cBu-CH(CH2 OCH3) 2,5-diCH.sub                       .3 -4-MeO-phenyl  868 1-cBu-CH(CH2 CH2 OCH3) 2,5-diCH3 -4-MeO-phenyl                        869 (cPr)2 CH 2-CH3 -4-MeO-5-F-phen                       yl  870 phenyl(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  871 2-furanyl(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  872 3-furan(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  873 2-thienyl(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  874 3-thienyl(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  875 2-isoxazolyl(cPr)CH 2-CH3 -4-MeO-5-F-phenyl  876 2-(5-CH3 -furanyl)(cPr)CH 2-CH3 -4-MeO-5-F-phenyl                        877 2-(4-CH3 -isoxazolyl)(cPr)CH                       2-CH3 -4-MeO-5-F-phenyl  878 cPr-CH(CH3) 2-CH3 -4-MeO-5-F-phenyl  879 1-cPr-CH(CH2 CH3) 2-CH3 -4-MeO-5-F-phenyl  880 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-5-F-phenyl                        881 1-cPr-CH(CH2 OCH3) 2-CH3                       -4-MeO-5-F-phenyl  882 l-cPr-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-5-F-phenyl                        883 (cBu)2 CH 2-CH3 -4-MeO-5-F-phen                       yl  884 phenyl(cBu)CH 2-CH3 -4-MeO-5-F-phenyl  885 2-furanyl(cBu)CH 2-CH3 -4-MeO-5-F-phenyl  886 3-furan(CBu)CH 2-CH3 -4-MeO-5-F-phenyl  887 2-thienyl(cBu)CH 2-CH3 -4-MeO-5-F-phenyl  888 3-thienyl(cBu)CH 2-CH3 -4-MeO-5-F-phenyl  889 2-isoxazolyl(aBu)CH 2-CH3 -4-MeO-5-F-phenyl  890 2-(5-CH3 -furanyl)(cBu)CH 2-CH3 -4-MeO-5-F-phenyl                        891 2-(4-CH3 -isoxazolyl)(cBu)CH                       2-CH3 -4-MeO-5-F-phenyl  892 cBu-CH(CH3) 2-CH3 -4-MeO-5-F-phenyl  893 1-cBu-CH(CH2 CH3) 2-CH3 -4-MeO-5-F-phenyl  894 1-cBu-CH(CH2 CH2 CH3) 2-CH3 -4-MeO-5-F-phenyl                        895 1-cBu-CH(CH2 OCH3) 2-CH3                       -4-MeO-5-F-phenyl  896 1-cBu-CH(CH2 CH2 OCH3) 2-CH3 -4-MeO-5-F-phenyl                        897 (cPr)2 CH 2,4,6-triCH3 -phenyl  898 phenyl(cPr)CH 2,4,6-triCH3 -phenyl  899 2-furanyl(cPr)CH 2,4,6-triCH3 -phenyl  900 3-furan(cPr)CH 2,4,6-triCH3 -phenyl  901 2-thienyl(cPr)CH 2,4,6-triCH3 -phenyl  902 3-thienyl(cPr)CH 2,4,6-triCH3 -phenyl  903 2-isoxazolyl(cPr)CH 2,4,6-triCH3 -phenyl  904 2-(5-CH3 -furanyl)(cPr)CH 2,4,6-triCH3 -phenyl  905 2-(4-CH3 -isoxazolyl)(cPr)CH 2,4,6-triCH3 -phenyl                        906 cPr-CH(CH3) 2,4,6-triCH3                       -phenyl  907 1-cPr-CH(CH2 CH3) 2,4,6-triCH3 -phenyl  908 l-cPr-CH(CH2 CH2 CH3) 2,4,6-triCH3 -phenyl                        909 l-cPr-CH(CH2 OCH3) 2,4,6-triCH.                       sub.3 -phenyl  910 l-cPr-CH(CH2 CH2 OCH3) 2,4,6-triCH3 -phenyl                        911 (cBu)2 CH 2,4,6-triCH3 -phenyl  912 phenyl(cBu)CH 2,4,6-triCH3 -phenyl  913 2-furanyl(cBu)CH 2,4,6-triCH3 -phenyl  914 3-furan(cBu)CH 2,4,6-triCH3 -phenyl  915 2-thienyl(cBu)CH 2,4,6-triCH3 -phenyl  916 3-thienyl(cBu)CH 2,4,6-triCH3 -phenyl  917 2-isoxazolyl(cBu)CH 2,4,6-triCH3 -phenyl  918 2-(5-CH3 -furanyl)(cBu)CH 2,4,6-triCH3 -phenyl  919 2-(4-CH3 -isoxazolyl)(cBu)CH 2,4,6-triCH3 -phenyl                        920 cBu-CH(CH3) 2,4,6-triCH3                       -phenyl  921 1-cBu-CH(CH2 CH3) 2,4,6-triCH3 -phenyl  922 1-cBu-CH(CH2 CH2 CH3) 2,4,6-triCH3 -phenyl                        923 1-cBu-CH(CH2 OCH3) 2,4,6-triCH.                       sub.3 -phenyl  924 1-cBu-CH(CH2 CH2 OCH3) 2,4,6-triCH3 -phenyl                        925 (cPr)2 CH 2,6-diMeO-pyrid-3-yl                        926 phenyl(cPr)CH 2,6-diMeO-pyrid-3-yl                        927 2-furanyl(cPr)CH 2,6-diMeO-pyrid-3-yl                        928 3-furan(cPr)CH 2,6-diMeO-pyrid-3-yl                        929 2-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl                        930 3-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl                        931 2-isoxazolyl(cPr)CH 2,6-diMeO-pyrid-3-yl  932 2-(5-CH3 -furanyl)(cPr)CH 2,6-diMeO-pyrid-3-yl  933 2-(4-CH3 -isoxazolyl)(cPr)CH 2,6-diMeO-pyrid-3-yl  934 cPr-CH(CH3) 2,6-diMeO-pyrid-3-yl  935 1-cPr-CH(CH2 CH3) 2,6-diMeO-pyrid-3-yl  936 1-cPr-CH(CH2 CH2 CH3) 2,6-diMeO-pyrid-3-yl  937 1-cPr-CH(CH2 OCH3) 2,6-diMeO-pyrid-3-yl  938 1-cPr-CH(CH2 CH2 OCH3) 2,6-diMeO-pyrid-3-yl  939 (cBu)2 CH 2,6-diMeO-pyrid-3-yl  940 phenyl(cBu)CH 2,6-diMeO-pyrid-3-yl  941 2-furanyl(cBu)CH 2,6-diMeO-pyrid-3-yl  942 3-furan(cBu)CH 2,6-diMeO-pyrid-3-yl  943 2-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl  944 3-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl  945 2-isoxazolyl(cBu)CH 2,6-diMeO-pyrid-3-yl  946 2-(5-CH3 -furanyl)(cBu)CH 2,6-diMeO-pyrid-3-yl  947 2-(4-CH3 -isoxazolyl)(cBu)CH 2,6-diMeO-pyrid-3-yl  948 cBu-CH(CH3) 2,6-diMeO-pyrid-3-yl  949 1-cBu-CH(CH2 CH3) 2,6-diMeO-pyrid-3-yl  950 1-cBu-CH(CH2 CH2 CH3) 2,6-diMeO-pyrid-3-yl  951 1-cBu-CH(CH2 OCH3) 2,6-diMeO-pyrid-3-yl  952 1-cBu-CH(CH2 CH2 OCH3) 2,6-diMeO-pyrid-3-yl  953 (cPr)2 CH 2,6-diCH3 -pyrid-3-yl  954 phenyl(cPr)CH 2,6-diCH3 -pyrid-3-yl  955 2-furanyl(cPr)CH 2,6-diCH3 -pyrid-3-yl  956 3-furan(cPr)CH 2,6-diCH3 -pyrid-3-yl  957 2-thienyl(cPr)CH 2,6-diCH3 -pyrid-3-yl  958 3-thienyl(cPr)CH 2,6-diCH3 -pyrid-3-yl  959 2-isoxazolyl(cPr)CH 2,6-diCH3 -pyrid-3-yl  960 2-(5-CH3 -furanyl)(cPr)CH 2,6-diCH3 -pyrid-3-yl  961 2-(4-CH3 -isoxazolyl)(cPr)CH 2,6-diCH3 -pyrid-3-yl                        962 cPr-CH(CH3) 2,6-diCH3 -pyrid-3-                       yl  963 1-cPr-CH(CH2 CH3) 2,6-diCH3 -pyrid-3-yl  964 1-cPr-CH(CH2 CH2 CH3) 2,6-diCH3 -pyrid-3-yl                        965 1-cPr-CH(CH2 OCH3) 2,6-diCH.sub                       .3 -pyrid-3-yl  966 1-cPr-CH(CH2 CH2 OCH3) 2,6-diCH3 -pyrid-3-yl                        967 (cBu)2 CH 2,6-diCH3 -pyrid-3-yl  968 phenyl(cBu)CH 2,6-diCH3 -pyrid-3-yl  969 2-furanyl(cBu)CH 2,6-diCH3 -pyrid-3-yl  970 3-furan(cBu)CH 2,6-diCH3 -pyrid-3-yl  971 2-thienyl(cBu)CH 2,6-diCH3 -pyrid-3-yl  972 3-thienyl(cBu)CH 2,6-diCH3 -pyrid-3-yl  973 2-isoxazolyl(cBu)CH 2,6-diCH3 -pyrid-3-yl  974 2-(5-CH3 -furanyl)(cBu)CH 2,6-diCH3 -pyrid-3-yl  975 2-(4-CH3 -isoxazolyl)(cBu)CH 2,6-diCH3 -pyrid-3-yl                        976 cBu-CH(CH3) 2,6-diCH3 -pyrid-3-                       yl  977 1-cBu-CH(CH2 CH3) 2,6-diCH3 -pyrid-3-yl  978 1-cBu-CH(CH2 CH2 CH3) 2,6-diCH3 -pyrid-3-yl                        979 1-cBu-CH(CH2 OCH3) 2,6-diCH.sub                       .3 -pyrid-3-yl  980 1-cBu-CH(CH2 CH2 OCH3) 2,6-diCH3 -pyrid-3-yl                        981 (cPr)2 CH 2-CH3 -6-MeO-pyrid-3-                       yl  982 phenyl(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  983 2-furanyl(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  984 3-furan(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  985 2-thienyl(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  986 3-thienyl(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  987 2-isoxazolyl(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl  988 2-(5-CH3 -furanyl)(cPr)CH 2-CH3 -6-MeO-pyrid-3-yl                        989 2-(4-CH3 -isoxazolyl)(cPr)CH                       2-CH3 -6-MeO-pyrid-3-yl  990 cPr-CH(CH3) 2-CH3 -6-MeO-pyrid-3-yl  991 1-cPr-CH(CH2 CH3) 2-CH3 -6-MeO-pyrid-3-yl  992 1-cPr-CH(CH2 CH2 CH3) 2-CH3 -6-MeO-pyrid-3-yl                        993 1-cPr-CH(CH2 OCH3) 2-CH3                       -6-MeO-pyrid-3-yl  994 1-cPr-CH(CH2 CH2 OCH3) 2-CH3 -6-MeO-pyrid-3-yl                        995 (cBu)2 CH 2-CH3 -6-MeO-pyrid-3-                       yl  996 phenyl(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  997 2-furanyl(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  998 3-furan(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  999 2-thienyl(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  1000  3-thienyl(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  1001  2-isoxazolyl(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl  1002  2-(5-CH3 -furanyl)(cBu)CH 2-CH3 -6-MeO-pyrid-3-yl                        1003  2-(4-CH3 -isoxazolyl)(cBu)CH                       2-CH3 -6-MeO-pyrid-3-yl  1004  cBu-CH(CH3) 2-CH3 -6-MeO-pyrid-3-yl  1005  1-cBu-CH(CH2 CH3) 2-CH3 -6-MeO-pyrid-3-yl  1006  1-cBu-CH(CH2 CH2 CH3) 2-CH3 -6-MeO-pyrid-3-yl  1007  1-cBu-CH(CH2 OCH3) 2-CH3 -6-MeO-pyrid-3-yl                        1008  1-cBu-CH(CH2 CH2 OCH3)                       2-CH3 -6-MeO-pyrid-3-yl  1009  (cPr)2 CH 4-CH3 -6-MeO-pyrid-3-yl  1010  phenyl(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1011  2-furanyl(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1012  3-furan(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1013  2-thienyl(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1014  3-thienyl(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1015  2-isoxazolyl(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl  1016  2-(5-CH3 -furanyl)(cPr)CH 4-CH3 -6-MeO-pyrid-3-yl                        1017  2-(4-CH3 -isoxazolyl)(cPr)CH                       4-CH3 -6-MeO-pyrid-3-yl  1018  cPr-CH(CH3) 4-CH3 -6-MeO-pyrid-3-yl  1019  1-cPr-CH(CH2 CH3) 4-CH3 -6-MeO-pyrid-3-yl  1020  1-cPr-CH(CH2 CH2 CH3) 4-CH3 -6-MeO-pyrid-3-yl  1021  1-cPr-CH(CH2 OCH3) 4-CH3 -6-MeO-pyrid-3-yl                        1022  1-cPr-CH(CH2 CH2 OCH3)                       4-CH3 -6-MeO-pyrid-3-yl  1023  (cBu)2 CH 4-CH3 -6-MeO-pyrid-3-yl  1024  phenyl(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1025  2-furanyl(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1026  3-furan(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1027  2-thienyl(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1028  3-thienyl(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1029  2-isoxazolyl(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl  1030  2-(5-CH3 -furanyl)(cBu)CH 4-CH3 -6-MeO-pyrid-3-yl                        1031  2-(4-CH3 -isoxazolyl)(cBu)CH                       4-CH3 -6-MeO-pyrid-3-yl  1032  cBu-CH(CH3) 4-CH3 -6-MeO-pyrid-3-yl  1033  1-cBu-CH(CH2 CH3) 4-CH3 -6-MeO-pyrid-3-yl  1034  1-cBu-CH(CH2 CH2 CH3) 4-CH3 -6-MeO-pyrid-3-yl  1035  1-cBu-CH(CH2 OCH3) 4-CH3 -6-MeO-pyrid-3-yl                        1036  1-cBu-CH(CH2 CH2 OCH3)                       4-CH3 -6-MeO-pyrid-3-yl  1037  (cPr)2 CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1038  phenyl(cPr)CH 4-CH3 -6-(CH3).                       sub.2 N-pyrid-3-yl  1039  2-furanyl(cPr)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1040  3-furan(cPr)CH 4-CH3 -6-(CH3)                       2 N-pyrid-3-yl  1041  2-thienyl(cPr)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1042  3-thienyl(cPr)CH 4-CH3 -6-(CH.sub.                       3)2 N-pyrid-3-yl  1043  2-isoxazolyl(cPr)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1044  2-(5-CH3 -furanyl)(cPr)CH                       4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1045  2-(4-CH3 -isoxazolyl)(cPr)CH                       4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1046  cPr-CH(CH3) 4-CH3 -6-(CH.sub.                       3)2 N-pyrid-3-yl  1047  1-cPr-CH(CH2 CH3) 4-CH3 -6-(CH3)2                       N-pyrid-3-yl  1048  1-cPr-CH(CH2 CH2 CH3) 4-CH3 -6-(CH3).sub.                       2 N-pyrid-3-yl  1049  1-cPr-CH(CH2 OCH3) 4-CH3 -6-(CH3)2                       N-pyrid-3-yl  1050  1-cPr-CH(CH2 CH2 OCH3) 4-CH3 -6-(CH3).sub                       .2 N-pyrid-3-yl  1051  (cBu)2 CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1052  phenyl(cBu)CH 4-CH3 -6-(CH3).                       sub.2 N-pyrid-3-yl  1053  2-furanyl(cBu)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1054  3-furan(cBu)CH 4-CH3 -6-(CH3)                       2 N-pyrid-3-yl  1055  2-thienyl(cBu)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1056  3-thienyl(cBu)CH 4-CH3 -6-(CH.sub.                       3)2 N-pyrid-3-yl  1057  2-isoxazolyl(cBu)CH 4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1058  2-(5-CH3 -furanyl)(cBu)CH                       4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1059  2-(4-CH3 -isoxazolyl)(cBu)CH                       4-CH3 -6-(CH3)2 N-pyrid-3-yl                        1060  cBu-CH(CH3) 4-CH3 -6-(CH.sub.                       3)2 N-pyrid-3-yl  1061  1-cBu-CH(CH2 CH3) 4-CH3 -6-(CH3)2                       N-pyrid-3-yl  1062  1-cBu-CH(CH2 CH2 CH3) 4-CH3 -6-(CH3).sub.                       2 N-pyrid-3-yl  1063  1-cBu-CH(CH2 OCH3) 4-CH3 -6-(CH3)2                       N-pyrid-3-yl  1064  1-cBu-CH(CH2 CH2 OCH3) 4-CH3 -6-(CH3).sub                       .2 N-pyrid-3-yl______________________________________
UTILITY

Compounds of this invention are expected to have utility in the treatment of inbalances associated with abnormal levels of CRF in patients suffering from depression, affective disorders, and/or anxiety.

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1108 of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFRl receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl2, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer.

After another centrifugation at 40,000g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10-10 -10-5 M), 100 μl of 125 I-ovine-CRF (125 I-o-CRF) (final concentration 150 pM) and 150 μl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of 125 I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values for inhibition which are then used to assess biological activity. Alternatively, tissues and cells which naturally express CRF receptors can be employed in binding assays analogous to those described above.

A compound is considered to be active if it has a Ki value of less than about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37 C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 C.), 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10-9 to 10-6 m) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/[32 P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [3 H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [32 p]cAMP from [32 P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal.

Dosage and Formulation

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

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Classifications
U.S. Classification546/273.4, 546/273.7, 548/304.4, 548/301.1, 548/310.4, 544/333
International ClassificationC07D235/26, A61P25/28, C07D405/04, C07D403/04, C07D235/08, C07D409/04, C07D401/04
Cooperative ClassificationC07D235/26, C07D401/04, C07D403/04, C07D405/04, C07D235/08, C07D409/04
European ClassificationC07D235/08, C07D235/26, C07D401/04, C07D409/04, C07D405/04, C07D403/04
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